1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors

ABSTRACT

The invention relates to compounds of Formula (I) as described herein, useful as histone deacetylase 6 (HDAC6) inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy.

TECHNICAL FIELD

The invention relates to 1,2,4-oxadiazole derivatives useful as histonedeacetylase 6 inhibitors. The invention also relates to pharmaceuticalcompositions comprising these compounds and to their use in therapy.

BACKGROUND

Histone deacetylases (HDACs) are part of a large family of enzymes thatcatalyze the removal of acetyl group from histones and non-histoneproteins. HDACs have crucial roles in numerous biological processes,largely through their repressive influence on transcription. In humans,there are four classes of HDACs which include a total of 18 proteins:class I HDACs are HDAC1, HDAC2, HDAC3 and HDAC8; class II HDACs areHDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10; class III HDACs areSir2-like proteins SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7;and class IV HDACs, which is HDAC11. The class II enzymes are furtherdivided into two subclasses, class IIa (HDAC4, HDAC5, HDAC7 and HDAC9)and class IIb (HDAC6 and HDAC10).

Histone deacetylase 6 (HDAC6) catalyzes primarily the deacetylation ofnon-histone substrates such as alpha-tubulin, heat shock protein (Hsp)90and cortactin.

HDAC6 activity has been reported to be involved in several pathologicalconditions, including cancer, neurological, ciliopathic, infectious,cardiovascular, infectious and immune and inflammatory diseases, asdiscussed in more detail below. HDAC6 inhibitors have thus emerged as anattractive therapeutic approach to treat a broad spectrum of diseases.

Many of the HDAC inhibitors currently in development are pan-HDACinhibitors, which are non-selective against different HDAC isoforms.Pan-HDAC inhibitors are known to exhibit significant side effects; inparticular, toxic side effects have been associated with inhibition ofcertain HDAC class I isoforms, particularly HDAC1 and HDAC2.

It would be advantageous to identify HDAC inhibitors that inhibit one ormore, but not all HDAC isoforms, and in particular compounds thatinhibit HDAC6 while not inhibiting or inhibiting to a much lower extentHDAC1 or HDAC2.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of Formula (I)as described below or a salt thereof:

whereinm is 0, 1 or 2;each R¹ is independently selected from halo, methyl and trifluoromethyl;A is selected from:

-   -   i) a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic        heteroaryl ring that is fully aromatic, and    -   ii) a 9- or 10-membered bicyclic heteroaryl ring consisting of a        5- or 6-membered monocyclic heteroaryl ring fused to a saturated        or partially unsaturated carbocyclic or heterocyclic ring,        wherein the 9- or 10-membered bicyclic heterocyclic ring is        linked to the rest of the molecule through the 5- or 6-membered        monocyclic heteroaryl ring,        wherein A contains one ring N atom at a position adjacent to the        ring atom through which ring A is attached to the rest of the        molecule, wherein A optionally contains from 1 to 3 additional        ring heteroatoms selected independently from N, O and S, and        wherein A is optionally substituted with one or two R² and in        addition A is optionally substituted with one R³;        each R² is independently selected from halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₃₋₇ cycloalkyl and —(C₁₋₆ alkylene)-OR⁴;        R³ is selected from -L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸, -L⁴-CONR⁹R¹⁰,        -L⁶-NR¹¹COR¹², —Y-L⁶-OR⁶ and —Y-L⁷- NR⁷R⁸;        L¹, L², L³, L⁴ and L⁵ are each independently selected from a        bond and C₁₋₆ alkylene;        L⁶ and L⁷ are each independently selected from C₂₋₆ alkylene;        each Y is independently selected from —O—, —NR¹³—, —CONR¹⁴— and        —NR¹⁵CO—;        each R⁴ is independently selected from hydrogen, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl and C₃₋₇ cycloalkyl-C₁₋₆ alkyl;        each R⁵ is independently selected from carbocyclyl, aryl,        heterocyclyl and heteroaryl, wherein the carbocyclyl, the aryl,        the heterocyclyl and the heteroaryl are each optionally        substituted with one or more R¹⁶;        R⁶ and R¹² are each independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl and -L¹-R⁵;        R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl, —(C₁₋₆ alkylene)-OR⁴ and -L¹-R⁵;        R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl, —(C₁₋₆ alkylene)-OR⁴ and -L¹-R⁵, or R⁹        and R¹⁰ taken together with the N atom to which they are        attached form a saturated 4- to 12-membered heterocyclic ring        optionally containing one additional heteroatom selected from N,        O and S, wherein said heterocyclic ring is optionally        substituted with one or more R¹⁶;        R¹¹, R¹³, R¹⁴ and R¹⁵ are each independently selected from        hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇        cycloalkyl-C₁₋₆ alkyl and —(C₁₋₆ alkylene)-OR⁴;        each R¹⁶ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —OH, —NR¹⁷R¹⁸,        —COR¹⁹, —CN, -L⁸-carbocyclyl, -L⁸-aryl, -L⁸-heterocyclyl and        -L⁸-heteroaryl, wherein the carbocyclyl in -L⁸-carbocyclyl, the        aryl in -L⁸-aryl, the heterocyclyl in -L⁸-heterocyclyl and the        heteroaryl in -L⁸-heteroaryl are each optionally substituted        with one or more R²⁰;        each L⁸ is independently selected from a bond and C₁₋₆ alkylene;        R¹⁷ and R¹⁸ are each independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl and C₃₋₇ cycloalkyl-C₁₋₆        alkyl;        R¹⁹ is selected from hydrogen, C₁₋₆ alkyl and C₁₋₆ haloalkyl;        and        each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —OH, —NR¹⁷R¹⁸,        —COR¹⁹ and —CN.

The compounds of Formula (I) as described herein are inhibitors ofHDACs, particularly HDAC6. These compounds, and pharmaceuticalcompositions comprising these compounds, are useful for the treatment ofdiseases associated with HDAC6. For example, the disease is cancer, anautoimmune or inflammatory disease, transplant rejection, a ciliopathy,a disease of the nervous system, a mental or behavioral disorder, aninfectious disease, a cardiovascular disease, muscle atrophy orcachexia.

The present invention further provides a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use as a medicament.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising said compound and a pharmaceutically acceptablecarrier, for use in the treatment of a disease associated with HDAC6.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of a disease associated with HDAC6.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for treating adisease associated with HDAC6.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use as a HDAC6 inhibitor.

The present invention further provides a method for treating a diseaseassociated with HDAC6, comprising administering a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.

The present invention further provides a method of inhibiting HDAC6activity, comprising administering to a patient in need of saidtreatment an amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, sufficient to inhibit HDAC6 activity.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising said compound and a pharmaceutically acceptablecarrier, for use in the treatment of a disease selected from cancer, anautoimmune or inflammatory disease, transplant rejection, a ciliopathy,a disease of the nervous system, a mental or behavioral disorder, aninfectious disease, a cardiovascular disease, muscle atrophy andcachexia.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of a disease selected from cancer, anautoimmune or inflammatory disease, transplant rejection, a ciliopathy,a disease of the nervous system, a mental or behavioral disorder, aninfectious disease, a cardiovascular disease, muscle atrophy andcachexia.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for treating adisease selected from cancer, an autoimmune or inflammatory disease,transplant rejection, a ciliopathy, a disease of the nervous system, amental or behavioral disorder, an infectious disease, a cardiovasculardisease, muscle atrophy and cachexia.

The present invention further provides a method for treating a diseaseselected from cancer, an autoimmune or inflammatory disease, transplantrejection, a ciliopathy, a disease of the nervous system, a mental orbehavioral disorder, an infectious disease, a cardiovascular disease,muscle atrophy and cachexia, comprising administering a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of Formula (I) or a saltthereof:

whereinm is 0, 1 or 2;each R¹ is independently selected from halo, methyl and trifluoromethyl;A is selected from:

-   -   i) a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic        heteroaryl ring that is fully aromatic, and    -   ii) a 9- or 10-membered bicyclic heteroaryl ring consisting of a        5- or 6-membered monocyclic heteroaryl ring fused to a saturated        or partially unsaturated carbocyclic or heterocyclic ring,        wherein the 9- or 10-membered bicyclic heterocyclic ring is        linked to the rest of the molecule through the 5- or 6-membered        monocyclic heteroaryl ring,        wherein A contains one ring N atom at a position adjacent to the        ring atom through which ring A is attached to the rest of the        molecule, wherein A optionally contains from 1 to 3 additional        ring heteroatoms selected independently from N, O and S, and        wherein A is optionally substituted with one or two R² and in        addition A is optionally substituted with one R³;        each R² is independently selected from halo, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₃₋₇ cycloalkyl and —(C₁₋₆ alkylene)-OR⁴;        R³ is selected from -L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸, -L⁴-CONR⁹R¹⁰,        -L⁵-NR¹¹COR¹², —Y-L⁶-OR⁶ and —Y-L⁷- NR⁷R⁸;        L¹, L², L³, L⁴ and L⁵ are each independently selected from a        bond and C₁₋₆ alkylene;        L⁶ and L⁷ are each independently selected from C₂₋₆ alkylene;        each Y is independently selected from —O—, —NR¹³—, —CONR¹⁴— and        —NR¹⁵CO—;        each R⁴ is independently selected from hydrogen, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, cycloalkyl and C₃₋₇ cycloalkyl-C₁₋₆ alkyl;        each R⁵ is independently selected from carbocyclyl, aryl,        heterocyclyl and heteroaryl, wherein the carbocyclyl, the aryl,        the heterocyclyl and the heteroaryl are each optionally        substituted with one or more R¹⁶;        R⁶ and R¹² are each independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl and -L¹-R⁵;        R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl, —(C₁₋₆ alkylene)-OR⁴ and -L¹-R⁵;        R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl, —(C₁₋₆ alkylene)-OR⁴ and -L¹-R⁵, or R⁹        and R¹⁰ taken together with the N atom to which they are        attached form a saturated 4- to 12-membered heterocyclic ring        optionally containing one additional heteroatom selected from N,        O and S, wherein said heterocyclic ring is optionally        substituted with one or more R¹⁶;        R¹¹, R¹³, R¹⁴ and R¹⁵ are each independently selected from        hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇        cycloalkyl-C₁₋₆ alkyl and —(C₁₋₆ alkylene)-OR⁴;        each R¹⁶ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —OH, —NR¹⁷R¹⁸,        —COR¹⁹, —CN, -L⁸-carbocyclyl, -L⁸-aryl, -L⁸-heterocyclyl and        -L⁸-heteroaryl, wherein the carbocyclyl in -L⁸-carbocyclyl, the        aryl in -L⁸-aryl, the heterocyclyl in -L⁸-heterocyclyl and the        heteroaryl in -L⁸-heteroaryl are each optionally substituted        with one or more R²⁰;        each L⁸ is independently selected from a bond and C₁₋₆ alkylene;        R¹⁷ and R¹⁸ are each independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl and C₃₋₇ cycloalkyl-C₁₋₆        alkyl;        R¹⁹ is selected from hydrogen, C₁₋₆ alkyl and C₁₋₆ haloalkyl;        and        each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —OH, —NR¹⁷R¹⁸,        —COR¹⁹ and —CN.

Embodiments of the present invention are outlined in the followingparagraphs. Each of the embodiments described below can be combined withany other embodiment described herein that is not inconsistent with theembodiment with which it is combined.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic administration to asubject).

Furthermore, each of the embodiments described herein envisions withinits scope the salts (for example pharmaceutically acceptable salts) ofthe compounds described herein. Accordingly, the phrase “or a saltthereof” (including also “or a pharmaceutically acceptable saltthereof”) is implicit in the description of all compounds describedherein. The invention also specifically relates to all compoundsdescribed herein in non-salt form.

In a compound of Formula (I) each R¹ is independently selected fromhalo, methyl and trifluoromethyl, and preferably each R¹ is fluoro. Itwill be understood that each substituent R¹ can be placed at anyavailable ring C atom of the pyridine ring to which R¹ is attached.

Preferably, in a compound of Formula (I) m is 0.

In a compound of Formula (I), A is a cyclic group selected from:

-   -   i) a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic        heteroaryl ring that is fully aromatic, and    -   ii) a 9- or 10-membered bicyclic heteroaryl ring consisting of a        5- or 6-membered monocyclic heteroaryl ring fused to a saturated        or partially unsaturated carbocyclic or heterocyclic ring,        wherein the 9- or 10-membered bicyclic heterocyclic ring is        linked to the rest of the molecule through the 5- or 6-membered        monocyclic heteroaryl ring,        wherein A contains one ring N atom at a position adjacent to the        ring atom through which ring A is attached to the rest of the        molecule, wherein A optionally contains from 1 to 3 additional        ring heteroatoms selected independently from N, O and S (and        wherein all remaining ring atoms of A are carbon atoms), and        wherein A is optionally substituted with one or two R² and in        addition A is optionally substituted with one R³. It will be        understood that ring A can be attached to the rest of the        molecule via a ring C atom or a ring N atom of A.

It will be understood that each substituent R² or R³ which is attachedto ring A can be placed at any available ring atom. In particular, anysubstituent R² or R³ (if present) can be attached to a ring C atom or aring N atom of A. It will further be understood that if ring A is abicyclic ring, the substituent(s) R² and/or R³ can each be attached toany available ring atom (e.g., any available ring C atom or anyavailable ring N atom) of any one of the rings constituting the bicyclicring group A. For example, if ring A is a bicyclic ring, the one or twooptional substituents R² (if present) and the optional substituent R³(if present) may be attached to the ring that does not contain the ringatom through which A is attached to the rest of the molecule, or saidoptional substituent(s) may be attached to the ring that contains thering atom through which A is attached to the rest of the molecule, orthe respective optional substituents may be attached to both ringsconstituting the bicyclic ring group A. Moreover, it will be understoodthat the one or two optional substituents R² (if present) and theoptional substituent R³ (if present) are typically each attached to adifferent ring atom of A. The attachment of two of these optionalsubstituents to the same ring atom of A is possible only if thecorresponding ring atom has enough available attachment sites. Forexample, if A is a 2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl ring (whichis composed of a pyridine ring fused to a pyrrolidine ring), a ring atom—CH₂— of the pyrrolidine moiety of the2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl ring may be substituted by twoof the aforementioned optional substituents (e.g., by two substituentsR², resulting in a ring atom —C(R²)(R²)—, or by one substituent R² andone substituent R³, resulting in a ring atom —C(R²)(R³)—).

Non-limiting examples of cyclic groups A include the groups listed inTable 1 below, and any tautomeric form thereof:

TABLE 1

wherein any of said A groups depicted in Table 1 is optionallysubstituted with one or two R² and in addition any of said A isoptionally substituted with one R³.

In some embodiments, in a compound of Formula (I), A is selected fromthe groups listed in Table 1 (including any tautomeric form thereof),wherein A is optionally substituted with one or two R² and in addition Ais optionally substituted with one R³.

Preferably, in a compound of Formula (I), A is selected from:

-   -   i) a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic        heteroaryl ring that is fully aromatic, and    -   ii) a 9- or 10-membered bicyclic heteroaryl ring consisting of a        5- or 6-membered monocyclic heteroaryl ring fused to a saturated        or partially unsaturated carbocyclic or heterocyclic ring,        wherein the 9- or 10-membered bicyclic heterocyclic ring is        linked to the rest of the molecule through the 5- or 6-membered        monocyclic heteroaryl ring,        wherein A contains one ring N atom at a position adjacent to the        ring atom through which ring A is attached to the rest of the        molecule, wherein A optionally contains from 1 to 3, preferably        1 or 2, additional ring N atoms (and wherein all remaining ring        atoms of A are carbon atoms), and wherein A is optionally        substituted with one or two R² and in addition A is optionally        substituted with one R³.

More preferably, in a compound of Formula (I), A is a 5- or 6-memberedmonocyclic or 9- or 10-membered bicyclic heteroaryl ring that is fullyaromatic, wherein A contains one ring N atom at a position adjacent tothe ring atom through which ring A is attached to the rest of themolecule, wherein A optionally contains from 1 to 3, preferably 1 or 2,additional ring N atoms (and wherein all remaining ring atoms of A arecarbon atoms), and wherein A is optionally substituted with one or two,preferably one, R² and in addition A is optionally substituted with oneR³.

Still more preferably, in a compound of Formula (I), A is selected fromthe cyclic groups listed below:

wherein A is optionally substituted with one or two, preferably one, R²and in addition A is optionally substituted with one R³.

It is particularly preferred that in a compound of Formula (I), A isselected from the cyclic groups listed below:

wherein A is optionally substituted with one or two, preferably one, R²and in addition A is optionally substituted with one R³.

In some embodiments, in a compound of Formula (I) A is substituted, i.e.at least one of the optional substituents R² and/or R³ is present. Saidsubstitutent(s) can be attached to any available ring atom of A(including any available ring N atom), as previously indicated. In someembodiments, in a compound of Formula (I), A is substituted with one R³and in addition is optionally substituted with one or two (preferablyone) R².

In some other embodiments, in a compound of Formula (I), A isunsubstituted (i.e. A does not have any optional substituent R² or R³).

In some preferred embodiments, in a compound of Formula (I), A is

wherein A is optionally substituted with one or two, preferably one, R²and in addition A is optionally substituted with one R³, wherein it ispreferred that A is substituted with one R³ and in addition isoptionally substituted with one or two, preferably one, R². In certainembodiments, A is substituted with one R³ and has no optionalsubstituent(s) R². Preferably, the substituent R³, if present, is placedat the ring C atom at position 4 or 5 of the pyridyl ring A, accordingto the numbering indicated in the chemical drawing below:

In some other preferred embodiments, in a compound of Formula (I), A is

wherein A is optionally substituted with one or two, preferably one, R²and in addition A is optionally substituted with one R³. Preferably, theone or two optional substituent(s) R² (if present) and the optionalsubstituent R³ (if present) are attached to the pyrrole ring formingpart of ring A. In certain embodiments, A is unsubstituted. Morepreferably, A is substituted with one R³ and in addition is optionallysubstituted with one or two, preferably one, R², wherein the substituentR³ and the one or two optional substituents R² (if present) arepreferably attached to the pyrrole ring forming part of ring A.

In some other preferred embodiments, in a compound of Formula (I), A is

wherein A is optionally substituted with one or two, preferably one, R²and in addition A is optionally substituted with one R³. Preferably, theone or two optional substituent(s) R² (if present) and the optionalsubstituent R³ (if present) are attached to the pyrrole ring formingpart of ring A. In certain preferred embodiments, A is unsubstituted. Incertain other preferred embodiments, A is substituted with one R³ and inaddition is optionally substituted with one or two, preferably one, R²,wherein the substituent R³ and the one or two optional substituents R²(if present) are preferably attached to the pyrrole ring forming part ofring A.

In some other preferred embodiments, in a compound of Formula (I), A is

wherein A is optionally substituted with one or two, preferably one, R²and in addition A is optionally substituted with one R³.

In some other preferred embodiments, in a compound of Formula (I), A is

wherein A is optionally substituted with one or two, preferably one, R²and in addition A is optionally substituted with one R³.

In some embodiments, in a compound of Formula (I), each R² isindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇cycloalkyl and —(C₁₋₄ alkylene)-OR⁴.

Preferably, in a compound of Formula (I), each R² is independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl and —(C₁₋₄ alkylene)-OR⁴. Insome embodiments, each R² is independently selected from C₁₋₄ alkyl and—(C₂₋₄ alkylene)-OR⁴. In some embodiments, one R² is selected frommethyl, ethyl, propyl and butyl (e.g., n-butyl). In some embodiments,one R² is —CH₂CH₂—OCH₃.

In some embodiments, in a compound of Formula (I), R³ is selected from-L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸, —CONR⁹R¹⁰, —NR¹¹COR¹² and —Y-L⁷-NR⁷R⁸,wherein preferably Y is selected from —O— and —NR¹³—.

In some preferred embodiments, in a compound of Formula (I), R³ is-L¹-R⁵, wherein preferably R⁵ is selected from heterocyclyl andheteroaryl, wherein the heterocyclyl and the heteroaryl are eachoptionally substituted with one or more R¹⁶.

In some preferred embodiments, in a compound of Formula (I), R³ is—CONR⁹R¹⁰ or —NR¹¹COR¹².

In some preferred embodiments, in a compound of Formula (I), R³ is—Y-L⁷-NR⁷R⁸, wherein Y is selected from —O— and —NR¹³—.

In some preferred embodiments, in a compound of Formula (I), R³ is —OR⁶,wherein R⁶ is -L¹-R⁵, wherein L¹ in said -L¹-R⁵ is preferably C₁₋₆alkylene, more preferably C₁₋₄ alkylene, and R⁵ in said -L¹-R⁵ ispreferably selected from heterocyclyl and heteroaryl, wherein theheterocyclyl and the heteroaryl are each optionally substituted with oneor more R¹⁶, or R³ is —NR⁷R⁸, wherein one of R⁷ or R⁸ is -L¹-R⁵, whereinL¹ in said -L¹-R⁵ is preferably C₁₋₆ alkylene, more preferably C₁₋₄alkylene, and R⁵ in said -L¹-R⁵ is preferably selected from heterocyclyland heteroaryl, wherein the heterocyclyl and the heteroaryl are eachoptionally substituted with one or more R¹⁶.

In some preferred embodiments, in a compound of Formula (I), R³ is-L²-OR⁶ or -L³-NR⁷R⁸, wherein L² and L³ are each independently selectedfrom C₁₋₆ alkylene, preferably C₁₋₄ alkylene.

In some embodiments, in a compound of Formula (I), R¹¹, R¹³, R¹⁴ and R¹⁵are each independently selected from hydrogen, C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, in a compound of Formula (I), each R¹⁶ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —OH, —NR¹⁷R¹⁸, —COR¹⁹, —CN and C₃₋₇ cycloalkyl.

A preferred embodiment relates to a compound of Formula (I), or a saltthereof, wherein:

A is a cyclic group selected from:

-   -   i) a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic        heteroaryl ring that is fully aromatic, and    -   ii) a 9- or 10-membered bicyclic heteroaryl ring consisting of a        5- or 6-membered monocyclic heteroaryl ring fused to a saturated        or partially unsaturated carbocyclic or heterocyclic ring,        wherein the 9- or 10-membered bicyclic heterocyclic ring is        linked to the rest of the molecule through the 5- or 6-membered        monocyclic heteroaryl ring,        and preferably A is a 5- or 6-membered monocyclic or 9- or        10-membered bicyclic heteroaryl ring that is fully aromatic,        wherein A contains one ring N atom at a position adjacent to the        ring atom through which ring A is attached to the rest of the        molecule, wherein A optionally contains from 1 to 3, preferably        1 or 2, additional ring N atoms (and wherein all remaining ring        atoms of A are carbon atoms), and wherein A is optionally        substituted with one or two R² and in addition A is optionally        substituted with one R³;        R³, if present, is selected from -L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸,        —CONR⁹R¹⁰, —NR¹¹COR¹² and —Y-L⁷-NR⁷R⁸, wherein preferably Y is        selected from —O— and —NR¹³—; and        wherein preferably m is 0.

A more preferred embodiment relates to a compound of Formula (I), or asalt thereof, wherein:

A is selected from the cyclic groups listed below:

and preferably A is selected from the cyclic groups listed below:

wherein A is optionally substituted with one or two, preferably one, R²and in addition A is optionally substituted with one R³;R³, if present, is selected from -L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸, —CONR⁹R¹⁰,—NR¹¹COR¹² and —Y-L⁷-NR⁷R⁸, wherein preferably Y is selected from —O—and —NR¹³—; andwherein preferably m is 0.

In a particularly preferred embodiment, the invention provides acompound of Formula (I), or a salt thereof, having formula (IIa) or(IIb):

wherein one of Z¹, Z² and Z³ is H and the others are independentlyselected from H and R², and preferably all of Z¹, Z² and Z³ are H; andwherein preferably R³ is selected from -L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸,—CONR⁹R¹⁰, —NR¹¹COR¹² and —Y-L⁷-NR⁷R⁸, and more preferably R³ isselected from —OR⁶, —NR⁷R⁸, —NR¹¹COR¹² and —Y-L⁷-NR⁷R⁸, whereinpreferably Y is selected from —O— and —NR¹³—; andwherein preferably m is 0. In certain preferred embodiments, in acompound of Formula (IIa) or (IIb) R³ is —NR¹¹COR¹². In certain otherpreferred embodiments, in a compound of Formula (IIa) or (IIb) R³ is—Y-L⁷-NR⁷R⁸ and Y is selected from —O— and —NR¹³—. In certain otherpreferred embodiments, in a compound of Formula (IIa) or (IIb) R³ is—OR⁶, wherein R⁶ is -L¹-R⁵, wherein L¹ in said -L¹-R⁵ is preferably C₁₋₄alkylene and R⁵ in said -L¹-R⁵ is preferably selected from heterocyclyland heteroaryl, wherein the heterocyclyl and the heteroaryl are eachoptionally substituted with one or more R¹⁶, or R³ is —NR⁷R⁸, whereinone of R⁷ or R⁸ is -L¹-R⁵, wherein L¹ in said -L¹-R⁵ is preferably C₁₋₄alkylene and R⁵ in said -L¹-R⁵ is preferably selected from heterocyclyland heteroaryl, wherein the heterocyclyl and the heteroaryl are eachoptionally substituted with one or more R¹⁶.

In another particularly preferred embodiment, the invention relates to acompound of Formula (I), or a salt thereof, having formula (IIIa) or(IIIb):

wherein one of Z¹, Z² and Z³ is R³ or H, preferably R³, and the othersare independently selected from H and R²;wherein preferably R³, if present, is selected from -L¹-R⁵, -L²-OR⁶,-L³-NR⁷R⁸, —CONR⁹R¹⁰, —NR¹¹COR¹² and —Y-L⁷-NR⁷R⁸, wherein preferably Yis selected from —O— and —NR¹³—, and more preferably R³ is selected from-L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸ and —CONR⁹R¹⁰, wherein preferably L² and L³are each independently selected from C₁₋₄ alkylene; andwherein preferably m is 0. In certain preferred embodiments, thecompound of Formula (I) is a compound of formula (IIIa). In certainpreferred embodiments, the compound of Formula (I) is a compound offormula (IIIb). In certain preferred embodiments, in a compound ofFormula (IIIa) or (IIIb) one of Z¹, Z² and Z³, preferably Z², is R³ andthe others are independently selected from H and R², and R³ is—CONR⁹R¹⁰. In certain other preferred embodiments, in a compound ofFormula (IIIa) or (IIIb) one of Z¹, Z² and Z³ is R³ and the others areindependently selected from H and R², and R³ is -L¹-R⁵, whereinpreferably R⁵ in said -L¹-R⁵ is selected from heterocyclyl andheteroaryl, wherein the heterocyclyl and the heteroaryl are eachoptionally substituted with one or more R¹⁶. In certain other preferredembodiments, in a compound of Formula (IIIa) or (IIIb) one of Z¹, Z² andZ³ is R³ and the others are independently selected from H and R², and R³is -L²-OR⁶ or -L³-NR⁷R⁸ wherein L² and L³ are each independentlyselected from C₁₋₄ alkylene.

In another particularly preferred embodiment, the invention relates to acompound of Formula (I), or a salt thereof, having formula (IVa):

wherein one of Z¹, Z², Z³ and Z⁴ is selected from R², R³ and H, and theothers are independently selected from H and R², with the proviso thatonly up to two of Z¹, Z², Z³ and Z⁴ are R²; andwherein preferably m is 0. In certain preferred embodiments, in acompound of Formula (IVa) Z⁴ is selected from R², R³ and H, and Z¹, Z²and Z³ are independently selected from H and R² with the proviso thatonly up to two of Z¹, Z², Z³ and Z⁴ are R², and wherein preferably Z³ isH. In certain preferred embodiments, in a compound of Formula (IVa) Z⁴is selected from R², R³ and H, and Z¹, Z² and Z³ are H.

In another particularly preferred embodiment, the invention relates to acompound of Formula (I), or a salt thereof, having formula (IVa-1):

wherein one of Z¹, Z² and Z³ is R³ or H, and the others areindependently selected from H and R², and preferably all of Z¹, Z² andZ³ are H; andwherein preferably m is 0.

In another particularly preferred embodiment, the invention relates to acompound of Formula (I), or a salt thereof, having formula (IVb):

wherein one of Z¹, Z², Z³ and Z⁴ is selected from R², R³ and H, and theothers are independently selected from H and R², with the proviso thatonly up to two of Z¹, Z², Z³ and Z⁴ are R²; andwherein preferably m is 0.

In another particularly preferred embodiment, the invention relates to acompound of Formula (I), or a salt thereof, having formula (IVb-1):

wherein one of Z¹, Z² and Z³ is R³ or H, and the others areindependently selected from H and R², andwherein preferably m is 0.

In certain embodiments, the invention provides a compound of Formula(I), or a salt thereof, selected from:

-   3-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-Propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   1-Butyl-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,-   N,N-Diethyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine,-   1-Butyl-N-ethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,-   4-(3-((4′-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propyl)morpholine,-   3-(5′-(3-(4,4-Difluoropiperidin-1-yl)propoxy)-[2,2′-bipyridin]-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(3-(Piperidin-1-ylmethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine,-   N-Butyl-3-methoxy-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)propanamide,-   N-(Cyclopropylmethyl)-N-methyl-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-amine,-   N1,N1-Diethyl-N3-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)propane-1,3-diamine,-   N-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-methyl-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-amine,-   N,N-Diethyl-3-(2-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)pyrimidin-5-yloxy)propan-1-amine,-   N1,N1-Diethyl-N3-methyl-N3-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-2,2′-bipyridin-5-yl)propane-1,3-diamine,-   3-(2-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N-Ethyl-N-phenethyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine,-   2-Phenyl-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)acetamide,-   3-(2-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(4′-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-[2,2′-bipyridin]-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   4-(2-((4′-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)[2,2′-bipyridin]-4-yl)oxy)ethyl)morpholine,-   N,N,1-Trimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,-   3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   1-Butyl-N,N-diethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,-   3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   2-(4,4-Difluoropiperidin-1-yl)-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)acetamide,-   N-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-amine,-   3-(2-(3-(Piperidin-1-ylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   1-Methyl-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)piperidine-4-carboxamide,-   3-Phenyl-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)propanamide,-   2-Cyclobutyl-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)acetamide,-   N-(Piperidin-3-yl)-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridine]-4-carboxamide,-   3-(5′-(3-(1H-Pyrazol-1-yl)propoxy)-[2,2′-bipyridin]-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   (1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methanol,    3-(2-(3-(Methoxymethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine,-   3-(2-(1H-Pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-(Pyridin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N-((1-Methylpiperidin-4-yl)methyl)-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridine]-4-carboxamide,-   N-((1-Methylpiperidin-4-yl)methyl)-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridine]-5-carboxamide,-   3-(2-(1-(1-(2,2,2-Trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-Methyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-Butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N-Methyl-3-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-2,2′-bipyridin-5-yloxy)propan-1-amine,-   1-(1-Butyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine,-   3-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)piperidine-3-carboxamide,-   1-(2-Methoxyethyl)-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,-   3-(2-(1-(2-Methoxyethyl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-Methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-(Pyridin-3-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-(Pyridin-2-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   2-(Methyl(3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propyl)amino)ethan-1-ol,-   3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(2-(2-Methoxyethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-Dimethyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine,-   3-(2-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-(2-(1-Methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,    and-   3-(2-(1-((1-Methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,    or a salt thereof.

Further examples of compounds of Formula (I) according to the inventioninclude the compounds shown below and salts thereof:

In a particularly preferred embodiment, the invention provides acompound of Formula (I), or a salt thereof, selected from

-   N,N-Diethyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine,-   1-Butyl-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,-   N,N,1-Trimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,-   3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   2-(4,4-Difluoropiperidin-1-yl)-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)acetamide,-   3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-(2-(1-Methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,    and-   3-(2-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,    or a salt thereof.

The invention also relates to any individual compound or any subgroup ofthe compounds recited in the lists above, and their salts.

Moreover, the present invention also relates to a compound of Formula(I), or a salt thereof, as described and defined herein (including anyof the preferred definitions/embodiments described herein above),wherein it is preferred that the following compounds are excluded fromFormula (I):

-   3-(2-(thiazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(2-methylthiazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)thiazole-2-carboxamide,-   3-(2-(oxazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(2-methyloxazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)oxazole-2-carboxamide,-   3-(2-(1H-imidazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1,2-dimethyl-1H-imidazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N,1-trimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-imidazole-2-carboxamide,-   3-(2-(1H-pyrrol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(5-methyl-1H-pyrrol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,-   3-(2-(1,2,4-thiadiazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1,2,4-thiadiazole-3-carboxamide,-   3-(2-(1,2,4-oxadiazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1,2,4-oxadiazole-3-carboxamide,-   3-(2-(1H-1,2,4-triazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(3-methyl-1H-1,2,4-triazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-1,2,4-triazole-3-carboxamide,-   3-(2-(1H-pyrazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(3-methyl-1H-pyrazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrazole-3-carboxamide,-   3-(2-(1H-1,2,3-triazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-1,2,3-triazole-1-carboxamide,-   3-(2-(4H-1,2,4-triazol-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide,-   3-(2-(1,3,4-oxadiazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide,-   3-(2-(1,3,4-thiadiazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide,-   3-(2-(2H-1,2,3-triazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-2H-1,2,3-triazole-2-carboxamide,-   3-(2-(2H-tetrazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(2-methyl-2H-tetrazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-2H-tetrazole-2-carboxamide,-   3-(2-(1,3,5-triazin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(4-methyl-1,3,5-triazin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1,3,5-triazine-2-carboxamide,-   3-(2-(pyridazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(6-methylpyridazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-6-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)pyridazine-3-carboxamide,-   3-(2-(pyrimidin-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(2-methylpyrimidin-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)pyrimidine-2-carboxamide,-   3-(2-(pyrazin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(5-methylpyrazin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)pyrazine-2-carboxamide,-   3-(2-(indolizin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1H-indol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1-methyl-1H-indazol-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(benzo[d]isothiazol-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)benzo[d]isoxazole,-   3-(2-(isoquinolin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,-   3-(2-(1,8-naphthyridin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,    and-   3-(2-(phthalazin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole.

Accordingly, it is preferred that the compounds mentioned in thepreceding sentence as well as salts and tautomers thereof are excluded.

Definitions of specific terms as used in the specification and claimsare provided below. All other technical and scientific terms used hereinand not defined below shall have the same meaning as commonly understoodby one of ordinary skill in the art to which this invention pertains. Inthe case of conflict, the present specification, including definitions,will control.

In the case of conflict between the chemical structures and names of thecompounds disclosed herein, the chemical structures will control.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges.

At various places in the present specification various aryl, heteroaryl,carbocyclyl and heterocyclyl groups are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “pyridyl”(or pyridinyl) may refer to a pyridin-2-yl, pyridin-3-yl or pyridin-4-ylring, and the term “piperidinyl” may refer to a piperidin-1-yl,piperidin-2-yl, piperidin-3-yl or piperidin-4-yl ring.

The term “n-membered” where n is an integer describes the number ofring-forming atoms in a ring system where the number of ring-formingatoms is n. For example, phenyl is an example of a 6-membered aryl,cyclopropyl is an example of a 3-membered carbocyclyl, pyrazolyl is anexample of a 5-membered heteroaryl, quinolinyl is an example of a10-membered heteroaryl, piperidinyl is an example of a 6-memberedheterocyclyl, and decahydroquinolinyl is an example of a 10-memberedheterocyclyl.

The term “C_(y-z)”, where y and z are integers, used in combination witha chemical group, designates a range of the number of carbon atoms inthe chemical group, with y and z being the endpoints, which areincluded. Examples include C₁₋₆, C₂₋₆, C₃₋₇ and the like.

The term “C_(y-z) alkyl” refers to a saturated straight or branchedacyclic hydrocarbon group having y to z carbon atoms. Thus, a C₁₋₆ alkylis an alkyl having from one to six carbon atoms. Examples of C₁₋₆ alkylinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,sec-pentyl, neopentyl, n-hexyl, or sec-hexyl.

The term “C_(y-z) alkoxy” refers to an C_(y-z) alkyl group (as definedabove) covalently linked to an oxygen atom, i.e. a group of formula—O-alkyl where the alkyl group has y to z carbon atoms. The term C₁₋₆alkoxy thus refers to an alkoxy group wherein the alkyl moiety has from1 to 6 carbon atoms. Examples of C₁₋₆ alkoxy include, but are notlimited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy or n-hexyloxy.

The term “C_(y-z) alkylene” refers to a saturated straight or brancheddivalent acyclic hydrocarbon group having from y to z carbon atoms.Thus, for example, a C₁₋₆ alkylene is an alkylene having from one to sixcarbon atoms. Preferably, said akylene groups are polymethylene groups,i.e. (CH₂)_(x), where x indicates the number of CH₂ units in therespective alkylene group, like from 1 to 6. Examples of a C₁₋₆ alkyleneinclude, but are not limited to, methylene, ethylene, propylene,n-butylene, n-pentylene or n-hexylene.

The term “aryl”, unless otherwise specified, refers to a 6- to18-membered hydrocarbon ring system which contains only hydrogen andcarbon atoms and which is monocyclic or multicyclic (e.g. fused, bridgedor spiro rings), wherein at least one of the rings in the ring system isaromatic. Aryl as used herein thus covers fully aromatic hydrocarbonring systems, i.e. where all the ring(s) in the system are aromatic,like phenyl, naphthyl or anthracyl, as well as ring systems in which anaromatic hydrocarbon ring (e.g. phenyl) is fused to one or morenon-aromatic (i.e. saturated or partially unsaturated) hydrocarbonrings, like indanyl, indenyl, 1-oxo-2,3-dihydro-1H-indenyl,tetrahydronaphthyl, fluorenyl and the like. In some embodiments, thepoint of attachment is on the aromatic hydrocarbon ring. In someembodiments, the aryl group has from 6 to 10 carbon atoms. In someembodiments, the aryl group is a fully aromatic hydrocarbon ring system.Preferably, the aryl group is phenyl. Aryl groups can be optionallysubstituted, as indicated elsewhere in the specification, and thesubstituent(s) may be placed at any available position in the ringsystem.

The term “bond” refers to a single bond, unless specifically indicatedotherwise.

The term “carbocyclyl”, unless otherwise specified, refers to a 3- to18-membered non-aromatic hydrocarbon ring system which contains onlyhydrogen and carbon atoms and which is monocyclic or multicyclic (e.g.fused, bridged or spiro rings). Each of the rings in the ring system isfully saturated or partially unsaturated, i.e. none of the rings isaromatic. One or more ring carbon atoms of a carbocyclyl group can eachbe optionally oxidized to form a CO group. In some embodiments,carbocyclyl contains from 3 to 10 carbon atoms. In some embodiments,carbocyclyl is a fully saturated hydrocarbon ring system, i.e. it doesnot contain any unsaturation; a fully saturated carbocyclyl is alsoreferred herein as “cycloalkyl”. Examples of carbocyclyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,decalinyl, and the like. Preferably, carbocyclyl is C₃₋₇ cycloalkyl.Carbocyclyl groups can be optionally substituted, as indicated elsewherein the specification, and the substituent(s) may be placed at anyavailable position in the ring system.

The term “C₃₋₇ cycloalkyl” refers to a monocyclic cycloalkyl having from3 to 7 ring-forming carbon atoms, and includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups can beoptionally substituted, as indicated elsewhere in the specification, andthe substituent(s) may be placed at any available position in the ringsystem.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. Preferably,halo is fluoro.

The term “C_(y-z) haloalkyl” refers to an alkyl group having from y to zcarbon atoms as defined herein which is substituted one or more timeswith one or more halo, which can be the same or different. Accordingly,a C₁₋₆ haloalkyl is a C₁₋₆ alkyl which is substituted one or more timeswith one or more halo. Haloalkyl groups include perhaloalkyl groups,i.e. alkyl groups where all hydrogen atoms are replaced by halo.Examples of haloalkyl groups include, but are not limited to,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,1-fluoro-2-fluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl,heptafluoropropyl, 4,4,4-trifluorobutyl chloromethyl, dichloromethyl,trichloromethyl difluorochloromethyl, dichlorofluoromethyl,1,2-dichloroethyl, 3,3-dichloropropyl and the like. In some embodiments,the haloalkyl is a fluoroalkyl, i.e. an alkyl group which is substitutedone or more times with one or more fluoro.

The term “C_(y-z) haloalkoxy” refers to an haloalkyl group having y to zcarbon atoms as defined herein covalently linked to an oxygen atom, i.e.a group of formula —O—C_(y-z) haloalkyl. A C₁₋₆ haloalkoxy group thusrefers to a haloalkoxy group wherein the haloalkyl moiety has from 1 to6 C atoms. Examples of haloalkoxy groups include, but are not limitedto, trifluoromethoxy, 2-fluoroethoxy, pentafluoroethoxy,3-chloropropoxy, 3-fluoropropoxy, heptafluoropropoxy, and the like.

The term “heteroaryl”, unless otherwise specified, refers to a 5- to18-membered heterocyclic ring system which is monocyclic or multicyclic(e.g. fused, bridged or spiro rings) and which comprises, in addition toC atoms, from 1 to 6 heteroatoms independently selected from N, O and S,wherein at least one of the rings in the ring system is aromatic andcontains at least one of the heteroatoms. Heteroaryl as used herein thuscovers fully aromatic ring systems, i.e. where all the ring(s) in thesystem are aromatic, like imidazolyl, pyridyl, quinolyl,pyrido[2,3-d]pyrimidinyl and the like, and groups in which anheteroaromatic ring(s) is fused to one or more non-aromatic (i.e.saturated or partially unsaturated) carbocyclic or heterocyclic rings,such as 5,6,7,8-tetrahydroquinoline,1,2,3,4-tetrahydro-1,8-naphthyridine and the like. The heteroatom(s) canbe optionally oxidized. Likewise, when the heteroaryl comprises aheteroaromatic ring fused to one or more non-aromatic carbocyclic orheterocyclic rings, one or more ring carbon atoms in the non-aromaticcarbocyclic or heterocyclic ring can each be optionally oxidized to forma CO group. The heteroaryl group can be attached to the rest of themolecule through any C or N atom that results in a stable structure. Insome embodiments, the point of attachment is on the heteroaromatic ring.In some embodiments, the heteroaryl group has from 1 to 4 heteroatoms.In some embodiments, the heteroaryl group has from 1 to 3 heteroatoms.In some embodiments, the heteroaryl is 5- to 6-membered monocyclic or 9-to 10-membered bicyclic. In some embodiments, the heteroaryl is 5- to6-membered monocyclic. In some embodiments, the heteroaryl group isfully aromatic. Nonlimiting examples of heteroaryl groups includepyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazine, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl,indolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzoxazolyl, cinnolinyl, indazolyl, indolizinyl, isoindolyl,pteridinyl, purinyl, furopyridinyl, acridinyl, phenazinyl,5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydro-1,8-naphthyridine andthe like. Heteroaryl groups can be optionally substituted, as indicatedelsewhere in the specification, and the substituent(s) may be placed atany available position in the ring system.

The term “heterocyclyl”, unless otherwise specified, refers to a 3- to18-membered partially unsaturated or fully saturated heterocyclic ringsystem which is monocyclic or multicyclic (e.g. fused, bridged or spirorings) which comprises, in addition to C atoms, from 1 to 6 heteroatomsindependently selected from N, O and S. Nitrogen or sulfur atoms may beoptionally oxidized (e.g., —N═O, —S(═O)—, or —S(═O)₂—) and additionallyone or more of the ring carbon atoms of the heterocyclyl may each beoptionally oxidized to form a CO group. “Heterocyclyl” as used hereinalso includes groups in which a partially unsaturated or fully saturatedheterocyclic ring is fused to one or more phenyl rings, as in1,2,3,4-tetrahydroquinolinyl, benzodioxolyl, carbazolyl or phthalimidyl.The heterocycyl can be attached to the rest of the molecule through anyring C or N atom that results in a stable structure. In someembodiments, the heterocyclyl is 3- to 7-membered monocyclic. Examplesof heterocyclyl groups include, but are not limited to, pyrrolidinyl,2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, homopiperidinyl, oxepanyl, thiepanyl, 2H-pyranyl, 4H-pyranyl,dioxanyl, 1,3-dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, oxazolidinyl, indolinyl,1-oxoisoindolinyl, decahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl,6-azabicyclo[3.3.1]heptanyl, 8-azabicyclo[3.2.1]octanyl,3-azaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonanyl, carbazolyl,phthalimidyl, tetrahydrothiopyranyl 1,1-dioxide, 2-azaspiro[4.5]decanyl,2,3-dihydrospiro[indene-1,4′-piperidinyl], and the like. Heterocyclylgroups can be optionally substituted, as indicated elsewhere in thespecification, and the substituent(s) may be placed at any availableposition in the ring system.

The term “optionally substituted” means unsubstituted or substituted. Asused herein, the term “substituted” means that a hydrogen atom isremoved and replaced by a monovalent substitutent. It is to beunderstood that substitution at a given atom is limited by valency.Unless defined otherwise (or limited by valency), a group that isoptionally substituted with “one or more” substituents may beunsubstituted or may, for example, carry one, two or three (particularlyone or two) substituents.

The term “CO” as used herein refers to a carbonyl group.

The term “partially unsaturated” as used herein in relation to a ringrefers to a ring that includes at least one double bond between ringatoms but is not fully unsaturated (i.e. aromatic).

The term “saturated” is used interchangeably with “fully saturated” andas used herein in relation to a ring it refers to a ring that does notcontain any unsaturation.

The term “fully aromatic” is used interchangeably with “aromatic” and asused herein in relation to a ring it refers to a ring that is fullyunsaturated.

A wavy line

in chemical drawings indicates the point of attachment to the rest ofthe molecule.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for said R.

The compounds of the invention may contain one or more asymmetriccenters and may thus give rise to stereoisomers. All stereoisomers, suchas enantiomers, diastereoisomers and mixtures thereof, are intendedunless otherwise indicated. Compounds of the present invention thatcontain asymmetrically substituted carbon atoms can be isolated inoptically active form or racemic mixtures. Methods on how to prepareoptically active forms from optically inactive starting materials areknown in the art, and include for example by resolution of racemicmixtures or by stereoselective synthesis.

The compounds presented herein may, in certain embodiments, exist astautomers. It should be understood that when compounds have tautomericforms, all tautomeric forms are intended to be included in the scope ofthe present invention. A “tautomer” refers to a molecule wherein aproton shift from one atom to another atom of the same molecule ispossible. Examples include ketone-enol pairs and annular forms where aproton can occupy two or more positions of a heterocyclic system as forexample in 1H- and 3H-imidazole. Tautomeric forms can be in equilibriumor sterically locked into one form by appropriate substitution.

Compounds of the invention include unlabeled forms of the compounds ofFormula (I) as well as isotopically labeled forms thereof. Isotopicallylabeled forms of the compounds are compounds that differ only in thereplacement of one or more atoms by a corresponding isotopicallyenriched atom. Examples of isotopes that can be incorporated intocompounds of the invention include for example isotopes of hydrogen,carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Suchisotopically labelled compounds are useful for example as probes inbiological assays, as analytical tools, or as therapeutic agents.

“Polymorphs” or “crystal forms” refers to crystal structures in which acompound (or a salt or solvate thereof) can crystallize in differentcrystal packing arrangements, all of which have the same elementalcomposition. Different crystal forms usually have different X-raydiffraction patterns, infrared spectra, Raman spectra, melting points,differential scanning calorimetry (DSC) spectra, crystal shape,solubility and/or stability, among others. When compounds of theinvention exist in different solid forms, all forms thereof, includingamorphous forms and crystal forms, are intended to be included in thescope of the present invention.

The terms “compound of the invention”, “compound as described herein”and the like are meant to include a compound of Formula (I) (includingeach and every subgenus of a compound of Formula (I) as described hereinand in the claims as well as the compounds described in the Examples),including all stereoisomers, tautomers, isotopically labeled forms andpolymorphs thereof.

The present invention also includes salts of the compounds of theinvention. Preferably, said salts are pharmaceutically acceptable salts.As used herein, a “pharmaceutically acceptable salt” is intended to meana salt that retains the biological effectiveness and properties of theparent compound (i.e. the free acid or free base, as applicable) andthat is not biologically or otherwise undesirable. Pharmaceuticallyacceptable salts include salts formed with inorganic or organic bases,and salts formed with inorganic and organic acids. Pharmaceuticallyacceptable salts are well known in the art. Exemplary pharmaceuticallyacceptable salts include those salts prepared by reaction of thecompounds of the present invention with a mineral or organic acid, suchas hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates,sulfites, bisulfites, phosphates, monohydrophosphates,dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides,iodides, nitrates, acetates, haloacetates (e.g. trifluoroacetates),propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4 dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,glycollates, tartrates, methane-sulfonates, ethane-sulfonates,propanesulfonates, benzenesulfonates, toluenesulfonates,trifluoromethansulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, mandelates, pyruvates, stearates, ascorbates,or salicylates. When the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g. sodium or potassium salts; alkaline earth metalsalts, e.g. calcium or magnesium salts; and salts formed with suitableorganic ligands such as ammonia, alkylamines, hydroxyalkylamines,lysine, arginine, N-methylglucamine, procaine and the like. Thepharmaceutically acceptable salts of the present invention can beprepared from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. For example, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in a suitablesolvent.

Additionally, compounds of the present invention, or salts thereof, mayexist in hydrated or unhydrated (anhydrous) form or as solvates withother solvent molecules. “Solvate” as used herein means solvent additionforms that contain either stoichometric or non-stoichometric amounts ofsolvent. Some compounds have a tendency to trap a fixed molar ratio ofsolvent molecules in the crystalline solid state, thus forming asolvate. If the solvent is water, the solvate formed is a hydrate.Non-limiting examples of solvates include hydrates and solvates withalcohols (also named alcoholates) such as ethanol (ethanolates). Whencompounds of the invention (or salts thereof) exist as solvates, allsolvates thereof are intended to be included in the scope of the presentinvention, particularly pharmaceutically acceptable solvates. As usedherein a “pharmaceutically acceptable solvate” is a solvate formed witha pharmaceutically acceptable solvent. Pharmaceutically acceptablesolvents are well known in the art and include solvents such as waterand ethanol.

Compounds of the invention, including salts thereof, can be preparedusing a number of synthetic routes, including the general syntheticroutes described below, starting from commercially available startingmaterials, compounds known in the literature, or from readily preparedintermediates, by employing standard synthetic methods and procedures.Standard synthetic methods and procedures for the preparation of organiccompounds and functional group transformations and manipulations areknown in the art and can be found in standard textbooks such as Smith M.B., “March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure”, 7^(th) Edition, Wiley, 2013; Greene T W and Wuts P G M“Greene's Protective Groups in Organic Synthesis”, 4^(th) edition,Wiley, 2006)

The reaction schemes described below are only meant as illustrative ofmethods to obtain the compounds of the invention. Other routes known bythe ordinary skilled artisan, as well as other reactants andintermediates, can also be used to arrive at the compounds of Formula(I).

In some of the processes described below it may be necessary oradvisable to protect reactive or labile groups with conventionalprotecting groups. Both the nature of these protecting groups and theprocedures for their introduction and removal are well known in the art(see for example Greene T W and Wuts P G M, cited supra). Whenever aprotecting group is present, a subsequent deprotection step will berequired, which can be performed under standard conditions well known inthe art, such as those described in the above reference.

Unless otherwise stated, in the methods described below the meanings ofthe different substituents in each synthetic intermediate and in eachcompound of Formula (I) are the meanings described above.

In general, the compounds of Formula (I) can be obtained following theprocedure shown in Scheme 1 below.

wherein R¹, m and ring A have the same meaning described for compound ofFormula (I), and M, T and X have the meaning defined below.

Ring A can be attached to the rest of the molecule via a ring C atom ora ring N atom of A. When ring A is attached via a ring C atom, compoundof Formula (XI) is obtained via a cross-coupling reaction of aorganometallic species (V) or (VIII) with a halide (VI) or (VII).

Several cross-coupling reactions can be used for the coupling of acompound of Formula (V) with a compound of Formula (VI) or a compound ofFormula (VII) with a compound of Formula (VIII), including: a Suzukicross coupling where M is a boronic acid or boron derivative and X isCl, Br or I; a Stille reaction where M is trialkylstannanyl group and Xis Cl, Br or I; a Negishi coupling where M is a zinc halide and X istriflate, Cl, Br or I; and a Hiyama coupling where M is a trialkylsilylgroup and X is Cl, Br or I.

When compounds of Formula (XI) are prepared through a Suzuki crosscoupling with the intermediates indicated in Scheme 1, the reaction canbe performed using a suitable Pd/ligand combination such as XPhos andPd₂(dba)₃ or Pd(PPh₃)₄, in the presence of a suitable Cu salt such asCu(OAc)₂ or CuI, in a suitable solvent such as tetrahydrofuran ordimethylformamide, using a suitable base such as potassium carbonate.The temperature of the reaction typically can go from room temperatureto 120° C. and the time of reaction typically from 1 h to 48 h. Examplesof boronic derivatives include among others diethyl, dimethyl,N-methyliminodiacetic acid (MIDA) derivative and2,2′-(phenylazanediyl)bis(ethan-1-ol) derivative.

When compounds of Formula (XI) are prepared through a Stille crosscoupling with the intermediates indicated in Scheme 1, the reaction canbe performed using a suitable Pd/ligand combination such as Pd(PPh₃)₄,Pd(PPh₃)Cl₂ or Pd(dppb)Cl₂ in the presence of a suitable Cu salt such asCuI or CuO, in the presence or absence of CsF, in a suitable solventsuch as tetrahydrofuran, dioxane or dimethylformamide. The temperatureof the reaction can typically go from room temperature to 120° C. andthe time of reaction typically from 1 h to 48 h. The organotin employedcan be trimethylstannyl derivative. An intermolecular Stifle Kellyreaction can also be used, in which both reagents are halo derivativesand are treated with (Bu₃Sn)₂, Et₄NI, and a Pd/ligand combination.

When compounds of Formula (XI) are prepared through a Negishi crosscoupling with the intermediates indicated in Scheme 1, the reaction canbe performed using a suitable Pd/ligand combination such as PPh₃ andPd₂(dba)₃, XPhos and Pd₂(dba)₃, RuPhos and Pd₂(dba)₃ or Pd(PPh₃)₄, in asuitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.The temperature of the reaction can typically go from room temperatureto 120° C. and the time of reaction typically from 1 h to 48 h.

When compounds of Formula (XI) are prepared through a Hiyama crosscoupling with the intermediates indicated in Scheme 1, the reaction canbe performed using a suitable Pd/ligand combination such as PdCl₂(PPh₃)₂and PPh₃ or Pd(OAc)₂ and di(1-adamantyl)-n-butylphosphine in thepresence of a suitable Cu salt such as CuI or CuBr, in the presence orabsence of tetrabutylammonium fluoride in a suitable solvent such astetrahydrofuran, dioxane or dimethylformamide. The temperature of thereaction can typically go from room temperature to 120° C. and the timeof reaction typically from 1 h to 48 h. When ring A is attached via aring N atom, compound of Formula (XI) is obtained by reaction of acompound of Formula (IX) and a compound of Formula (X) (wherein the ringN atom in A that will form the bond to the rest of the molecule is in NHform) through a cross coupling reaction or alternatively, between acompound of Formula (VII) and a compound of Formula (X) through adisplacement reaction. In the case of a cross-coupling reaction, theChan-Lam reaction can be used for the coupling of a compound of Formula(IX) with a compound of Formula (X). This reaction allowscarbon-heteroatom bond formation via an oxidative coupling of boronicacids, stannanes or siloxanes with N—H containing compounds in thepresence of air. T in compounds of Formula (IX) is a boron, tin orsilicon derivative. The reaction is induced by a stoichiometric orcatalytic amount of copper salt such as Cu(OAc)₂ or CuI, in the presenceor absence of a base such as NEt₃, pyridine or DMAP in a suitablesolvent such as CH₂Cl₂, pyridine or DMSO in the presence of air. Thetemperature of the reaction can typically go from room temperature to120° C. and the time of reaction typically from 1 h to 48 h.Alternatively, a compound of formula (XI) can be obtained bydisplacement reaction between a compound of Formula (VII) and a compoundof Formula (X), which can be carried out in the presence of a base suchas CsCO₃, tBuOK, K₂CO₃ NaH or pyridine and in the presence or absence ofcopper derivative such as Cu₂O or CuI in a suitable solvent such as DMF,DMSO or THF. The temperature of the reaction can typically go from roomtemperature to 120° C. and the time of reaction typically from 1 h to 48h.

Compounds of Formula (I) are obtained in two steps from a cyanoderivative of Formula (XI). In a first step, the cyano derivative ofFormula (XI) is transformed into the N′-hydroxyimidamide of Formula(XII) by reaction with hydroxylamine, which is then followed bycondensation of (XII) with trifluoroacetic anhydride to give a compoundof Formula (I). Addition of hydroxylamine to cyano derivatives (XI) iscarried out in a suitable solvent such as EtOH or MeOH, and in thepresence of base in the case hydroxylamine chlorhydrate is used. Thetemperature of the reaction can typically go from room temperature to60° C. and the time of reaction typically from 1 h to 48 h. Thecondensation of N′-hydroxyimidamides (XII) with trifluoroaceticanhydride in a suitable solvent such as CH₂Cl₂ or THF gives thecorresponding N′-trifluoroacethyloxyimidamide that in the same reactionmedium or after the addition of trilfuoroacetic acid yield1,2,4-oxadiazoles of Formula (I).

Alternatively, compounds of Formula (I) can also be prepared in threesteps building the 1,2,4-oxadiazole from cyano derivative (VII) beforethe cross-coupling or displacement reaction with appropriate ring Aderivatives. Reaction of cyano derivative (VII) with hydroxylamine givesintermediate (XIII) that is then condensed with trifluoroaceticanhydride to give a compound of formula (XIV), which is then subjectedto cross coupling or displacement reactions with an appropriate ring Aderivative to give a compound of Formula (I), as outlined in Scheme 2.When a cross-coupling reaction is used to convert a compound (XIV) to acompound of Formula (I), organometallic species can be generated eitherfrom a haloderivative of formula (XIV) or from appropriate ring Aderivatives, as in Scheme 1. The reactions outlined in Scheme 2 can beperformed under the same reaction conditions described above for Scheme1.

wherein R¹, m and ring A have the same meaning described for compound ofFormula (I), and X has the meaning defined above.

The compounds of Formula (V), (VI), (VII), (VIII), (IX), and (X) arecommercial or can be obtained following standard procedures well knownto those skilled in the art of organic chemistry.

Organometallic derivatives of Formula (V), (VIII), (IX) and thosederived from compounds of Formula (XIV) can be obtained from compoundsof Formula (VII) and (XIV) by transmetallation following standardprocedures in the preparation of reagents for Suzuki, Stille Hiyama,Negishi and Chan-Lam couplings, well known to those skilled in the artof organic chemistry. For example, N-methyliminodiacetic acid boronatederivatives can be prepared by reaction of compounds of Formula (VII)and (XIV) with nBuLi in the presence of B(OiPr)₃ at −78° C. followed bythe addition of N-methyliminodiacetic acid; trimethyltin derivatives canbe prepared by reaction of compounds of Formula (VII) and (XIV) withhexamethylditin and Pd (PPh₃)₄ in toluene at 110° C. for 16 h;organozinc derivatives can be prepared from compounds of Formula (VII)and (XIV) by treatment with Zn in THF at room temperature for 1 to 6 h;and trimetilsilyl derivatives can be prepared by reaction of compoundsof Formula (VII) and (XIV) with nBuLi in the presence oftrimethylsylchloride at −78° C. in THF.

Introduction of substituents R² and R³ onto ring A as well astransformations in R² and R³ substituents of ring A can be donefollowing standard procedures well known to those skilled in the art oforganic chemistry. Said standard procedures include, for example: thesubstitution of a primary or secondary amines by treatment with analkylating agent under standard conditions; or by reductive amination,i.e. by treatment with an aldehyde or a ketone in the presence of areducing agent such as sodium cyanoborohydride or sodiumtriacetoxyborohydride; the conversion of an amine into an amide by meansof activating agents such us dicyclohexyl carbodiimide (DCC),1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu),1-ethyl-3-(3′-dimethylamino)carbodiimide (EDC) in the presence of abase, such as, disopropylethylamine, pyridine, thriethylamine, orN-methylmorpholine, in a solvent, such as dimethoxyethane,N,N-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane oralternatively, by reaction with acid chlorides in the presence of asuitable base; the alkylation of an amide by treatment with analkylating agent under basic conditions; the conversion of an alcoholinto an ether under standard conditions; the partial or total oxidationof an alcohol to give a ketone under standard oxidizing conditions; thereduction of a ketone by treatment with a reducing agent such as sodiumborohydride; the conversion of an alcohol into a halogen by reactionwith SOCl₂, PBr₃, tetrabutylammonium bromide in the presence of P₂O₅, orPCl₃; the conversion of halogen into an amine by reaction with an amine,optionally in the presence of a suitable solvent, and preferablyheating; and the conversion of a primary amide into a —CN group understandard conditions.

Likewise, any of the aromatic rings of the compounds of the presentinvention can undergo electrophilic aromatic substitution reactions ornucleophilic aromatic substitution reactions, widely described in theliterature.

Some of these interconversion reactions are explained in greater detailin the examples. As it will be obvious to those skilled in the art,these interconversion reactions can be carried out upon a compound ofFormula (I), thus generating further compounds of Formula (I), as wellas upon any suitable synthesis intermediate thereof.

The salts of a compound of Formula (I) can be obtained during the finalisolation and purification of the compounds of the invention or can beprepared by treating a compound of Formula (I) with a sufficient amountof the desired acid (or base) to give the salt in a conventional manner.

Where the processes for the preparation of the compounds of theinvention give rise to mixtures of stereoisomers, individualstereoisomers of a compound of Formula (I) can be obtained for exampleby resolution, starting from a compound of formula (I) obtained as amixture of stereoisomers, using well known methods such as formation ofdiastereomeric pairs by salt formation with an optically active acidfollowed by fractional crystallization and regeneration of the freebase, or by chiral preparative chromatography. Alternatively, it ispossible to obtain optically pure or enantiomerically enriched syntheticintermediates, which can then be used as such in subsequent steps, atvarious stages of the synthetic procedures described above, using anyknown method for chiral resolution. Alternatively, it is possible toobtain optically pure or enantiomerically enriched final compounds (orsynthetic intermediates) by using chiral chromatography.

The compounds of the invention inhibit the activity of histonedeacetylases. In particular, the compounds of the invention have beenfound to be potent inhibitors of HDAC6. The activity of the compounds ofthe invention as HDAC6 inhibitors can be determined using for examplethe in vitro assays described in the Examples section. In particular,Example 8 describes a method to determine HDAC6 inhibitory activity. Thecompounds of the invention have been found to be potent HDAC6 inhibitorsusing the assay described in Example 8. Compounds of the invention havealso been shown to inhibit HDAC6 activity in cells, as shown by theresults described in Example 9. Selectivity towards HDAC6 compared toother HDAC isoforms can be assayed using methods well known in the art,for example in vitro assays similar to the one described in Example 8using the corresponding HDAC isoform of interest. Compounds of theinvention have been found to exhibit selectivity towards HDAC6 vs HDAC2,as shown by the results in Example 8 against HDAC2 using representativecompounds of the invention.

HDAC6 is a class IIb HDAC that can deacetylate substrates, such astubulin, heat shock protein (Hsp)90 and cortactin. HDAC6 localizes inthe cytosol and possesses two catalytic domains and a C-terminal zincfinger domain that can bind free ubiquitin as well mono- andpolyubiquitinated proteins (Li et al, FEBS J. 2013 February;280(3):775-93). The ubiquitin-binding domain in HDAC6 associates withseveral proteins involved in the control of the ubiquitin, proteasomesystem, aggresome formation and autophagy. Additionally, the ability ofHDAC6 to deacetylate alpha-tubulin affects microtubule-mediatedprocesses such as cell migration, immune synapse formation, viralinfection, the degradation of misfolded proteins and of stress granule.HDAC6 has also been shown to deacetylate Hsp90 and modulate itschaperone activity, thus modulating various Hsp90-associated cellsignaling pathways such as the control of stress-related response.

Many studies have reported the role of HDAC6 in cancer. For example,inhibition of HDAC6 was shown to reduce growth of multiple myeloma inpreclinical models and to enhance the effect of proteasome inhibitorsand thalidomide-based Immunomodulatory drugs used as standards of care(Santo et al, Blood. 2012 Mar. 15; 119(11):2579-89; North et al, PLoSOne. 2017 Mar. 6; 12(3):e0173507). Inhibition of HDAC6 was also shown toincrease the effect of other standard of care drugs such as paclitaxelin ovarian, pancreatic and breast cancer cells (Huang et al, Oncotarget2017 Jan. 10; 8(2):2694-2707). The antiproliferative activity of HDAC6inhibitors has also been observed in prostate cancer and melanoma cells(Li et al, Eur J Med Chem. 2015 Jul. 15; 100:270-6; Seidel et al,Biochem Pharmacol. 2016 Jan. 1; 99:31-52). In addition, in vivo efficacyof HDAC6 inhibitors has been reported in colorectal, inflammatory breastcancer, leukemia, lymphoma and ARID1A mutant ovarian xenograft models(Yang et al, J Med Chem. 2016 Feb. 25; 59(4):1455-70; Putcha et al,Breast Cancer Res, 2015 Dec. 8; 17(1):149; Bitler et al, Nat Cell Biol.2017 August; 19(8):962-973). Similarly, HDAC6 knock down reduces uterineleiomyoma and gastric cancer cell proliferation, while HDAC6overexpression promotes proliferation and promotes drug-resistance ofnon-small cell lung cancer cells and glioblastoma cells (Wei et al,Reprod Sci. 2011 August; 18(8):755-62; Park et al, Cancer Lett. 2014Nov. 1; 354(1):97-106; Wang et al, Oncol Rep. 2016 July; 36(1):589-97;Wang et al, Cancer Lett. 2016 Aug. 28; 379(1):134-42). Furthermore,HDAC6 inhibitors were shown to have anticancer activity by stimulatingthe immune-response against the tumors in models of melanoma andnon-small cell lung cancer when used alone or in combination withimmune-checkpoints inhibitors or epigenetic modulators (Knox et al,Abstract 4055, AACR Annual Meeting 2017; Apr. 1-5, 2017; Washington,D.C.; Woan et al, Mol Oncol. 2015 August; 9(7):1447-1457; Tavares et al,ACS Med Chem Lett. 2017 Sep. 5; 8(10):1031-1036; Adeegbe et al, CancerDiscov. 2017 August; 7(8):852-867).

HDAC6 has also been widely reported to play a role in inflammatory andautoimmune diseases. Knock out mice for HDAC6 have an increased numberof circulating regulatory T cells (Tregs), which are key to themaintenance of immune homeostasis. Likewise, HDAC6 specific inhibitorspromote Treg suppressive activity in models of inflammatory boweldisease and graft versus host disease (de Zoeten et al, Mol Cell Biol.2011 May; 31(10):2066-78). HDAC6 inhibitors were shown to have diseasemodifying activity in models of inflammation, rheumatoid arthritis andsystemic lupus erythematosus (Vishwakarma et al, Int Immunopharmacol.2013 May; 16(1):72-8; Regna et al, Clin Immunol. 2016 January;162:58-73). Mice lacking HDAC6 display reduction of autophagy, whichameliorates chronic obstructive pulmonary disease (COPD)-associatedcilia dysfunction (Lam et al, J Clin Invest. 2013 December;123(12):5212-30).

HDAC6 inhibitors have also been reported to be effective to treatciliopathies. Ciliopathies are genetic diseases associated with defectsin ciliary structure or function, and include, among others, polycystickidney disease, polycystic liver disease, Bardet-Biedl syndrome andretinal degeneration. In a model of polycystic kidney disease, HDAC6inhibitors prevented cyst formation and improved renal function(Cebotaru et al, Kidney Int. 2016 July; 90(1):90-9). Similarly, in amodel of polycystic liver disease, pharmacological inhibition of HDAC6decreased proliferation of cystic cholangiocytes, and diminished livercyst development and fibrosis (Gradilone et al, Am J Pathol. 2014 March;184(3):600-8).

HDAC6 has also been shown to have an important role in diseases of thenervous system. In particular, HDAC6 inhibitors showed efficacy inmodels of peripheral neuropathies such as Charcot-Marie-Tooth diseaseand chemotherapy-induced peripheral neuropathy (Benoy et al,Neurotherapeutics. 2017 April; 14(2):417-428; Krukowski et at, Pain.2017 June; 158(6):1126-1137). In addition, in neuronal culture derivedfrom patients with amyotrophic lateral sclerosis, treatment with HDAC6inhibitors rescued their defective phenotype (Guo et al, Nat Commun.2017 Oct. 11; 8(1):861).

HDAC6 inhibitors have also been reported to be effective to treatseveral other diseases of the nervous system. For example, reduction orinhibition of HDAC6 has been shown to rescue memory and improvecognition in mouse models of Alzheimer's disease (Govindarajan et al,EMBO Mol Med. 2013 January; 5(1):52-63) Loss or inhibition of HDAC6suppresses neuritic tau accumulation, thus HDAC6 inhibition could beuseful to treat not only Alzheimer's disease but also other human4-repeat tauopathies such as corticobasal degeneration and progressivesupranuclear palsy (Tseng et al, Cell Rep. 2017 Aug. 29;20(9):2169-2183). Furthermore, in a model of Huntington's disease, HDAC6inhibition reduces the vulnerability of neurons to mutant huntingtin,thus suggesting a neuroprotective effect of HDAC6 inhibitors in HD(Guedes-Dias et al, Biochim Biophys Acta. 2015 November;1852(11):2484-93).

HDAC6 has also been reported to play a role in mental and behaviouraldisorders such as depression. For example, HDAC6 inhibitors stimulatedthe mouse exploratory behaviors and had a positive effect in anxiolyticand social interaction tests (Jochems et al, Neuropsychopharmacology.2014 January; 39(2):389-400).

Moreover, several publications underline the important role of HDAC6 ininfectious diseases. The use of HDAC6 inhibitors reduced the replicationof viruses such as Japanese Encephalitis Virus (JEV), hepatitis C virus(HCV) and Rabies Virus (Lu et al, Int J Mol Sci. 2017 May 1; 18(5); Zanet al, Front Cell Infect Microbial. 2017 Apr. 26; 7:146; Ai et al, J MedChem. 2015 Jan. 22; 58(2):785-800). HDAC6 was also shown to facilitatecell entry of influenza A viruses and to control the viral lytic-latencyswitch of other viruses (Banerjee et al, Science 2014 Oct. 24;346(6208):473-7). For example, HDAC6 was reported to be involved in themaintenance of HIV latency, thus inhibition of HDAC6 could promote thebody clearance of the virus (Huo et al, J Biol Chem. 2011 Mar. 18;286(11):9280-6). Furthermore, selective HDAC6 inhibitors improvedsurvival and bacterial clearance in models of sepsis (Zhao et al, JTrauma Acute Care Surg. 2016 January; 80(1):34-40).

Several publications have also reported a role of HDAC6 incardiovascular diseases. Knockout mice for HDAC6 display improved heartcondition in mouse models of heart failure. Moreover, HDAC6 null miceare resistant to skeletal muscle wasting considered a life threateningcomplication in congestive heart failure (Demos-Davies et al, Am JPhysiol Heart Circ Physiol. 2014 Jul. 15; 307(2):H252-8).Pharmacological inhibition of HDAC6 was shown to protect against atrialremodeling in connection to atrial fibrillation (Zhang et al,Circulation. 2014 Jan. 21; 129(3):346-58). HDAC6 activity wasconsistently increased in stressed myocardium, thus suggesting a rolefor HDAC6 inhibitors in myocardiopathies (Lemon et al, J Mol CellCardiol. 2011 July; 51(1):41-50). Selective inhibition of HDAC6 has alsobeen reported to improve survival in a rodent model of hemorrhagic shock(Chang et al, J Trauma Acute Care Surg. 2015 December; 79(6):905-10).Furthermore, inhibition of HDAC6 improved established pulmonary arteryhypertension in experimental models and exerts a neuroprotective effectin models of brain ischemia (Boucherat et al, Sci Rep. 2017 Jul. 3;7(1):4546; Liesz et al, J Neurosci. 2013 Oct. 30; 33(44):17350-62).

The compounds of the invention are thus expected to be useful fortreating diseases associated with HDACs, in particular HDAC6. Examplesof diseases associated with HDAC6 include, without limitation, thediseases listed below:

Cancers, such as: lung cancer, colon cancer, breast cancer, prostatecancer, liver cancer, brain cancer and others CNS neoplasms, kidneycancer, ovarian cancer, stomach cancer, skin cancer, bone cancer,gastric cancer, pancreatic cancer, cardiac cancer, glioma, glioblastoma,esophageal cancer, hepatocellular carcinoma, bone and joint cancer,papillary renal carcinoma, head and neck squamous cell carcinoma,sarcomas, mesothelioma, leukemias, lymphomas, and myelomas;

Autoimmune or inflammatory diseases, such as: rheumatoid arthritis,osteoarthritis, rheumatoid spondylitis, psoriatic arthritis, infectiousarthritis, progressive chronic arthritis, deforming arthritis, traumaticarthritis, gouty arthritis, Reiter's syndrome, polychondritis, acutesynovitis and spondylitis, psoriasis, post ischemic perfusion injury,inflammatory bowel disease (e.g. ulcerative colitis or Crohn's disease),eczema, ischemia/reperfusion injury, glomerulonephritis, hemolyticanemia, aplastic anemia, idiopathic thrombocytopenia, neutropenia,chronic thyroiditis, Graves' disease, diabetes type I, schleroderma,diabetes, hepatitis, primary binary cirrhosis, systemic inflammatoryresponse syndrome, postoperative or posttraumatic inflammation,myasthenia gravis, pemphigus, alcoholic liver disease, cystic fibrosis,multiple sclerosis (MS), Addison's disease, Castleman's disease,polyarteritis nodosa, systemic lupus erythematosus, atopic dermatitis,contact dermatitis, chronic renal insufficiency, Stevens-Johnsonsyndrome, idiopathic sprue, sarcoidosis, Guillain-Barre syndrome,uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontaldisease, pulmonary interstitial fibrosis, acute respiratory distresssyndrome, asthma, bronchitis, rhinitis, sinusitis, pancreatitis,inflammatory bone disease, meningitis, cystitis, pharyngolaryngitis,pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema,chronic obstructive pulmonary disease (COPD), pulmonary fibrosis,silicosis, chronic inflammatory pulmonary disease, or peritonealfibrosis;

Transplant rejection, including host versus graft disease, graft versushost disease and allograft rejection. Infectious diseases, includinginfluenza, viral encephalitis, HIV, hepatitis of viral origin, pneumoniaand sepsis. Ciliopathies, such as polycystic kidney disease, polycystickidney disease, Alstrom syndrome, Bardet-Biedl syndrome, some forms ofretinal degeneration, Joubert syndrome, Meckel-Gruber syndrome,nephronophthisis, orofaciodigital syndrome 1, Senior-Loken syndrome,primary ciliary dyskinesia (Kartagener Syndrome), orasphyxiatingthoracic dysplasia (Jeune), Marden-Walker syndrome, or isomerism;

Diseases of the nervous system, such as Wilson's disease, prion disease,Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, amyloidosis, Alzheimer's disease, Alexander's disease, Pick'sDisease, spinal muscular dystrophy, Lewy body dementia,chemotherapy-induced cognitive dysfunction, mitochondrialencephalomyopathies and gut dysmotility syndromes, motor neurogenesisdisease (MND), ataxia syndromes including Friedreich's ataxia andspinocerebellar ataxia (SCA), spinal cord injury, olivopontocerebellaratrophy, multiple system atrophy, progressive supranuclear palsy,synucleinopathies, Down Syndrome, corticodentatonigral degeneration,progressive familial myoclonic epilepsy, strionigral degeneration,torsion dystonia, familial tremor, Gilles de la Tourette syndrome,Shy-Drager syndrome and Hallervorden-Spatz disease, as well asperipheral neuropathies such as Charcot-Marie Tooth Disease, peripheralneuropathy induced by chemotherapeutic agents (e.g. platinum-basedchemoterapeutic, taxane, vincristine, bortezomib, etc.) and the like;

Mental and behavioral disorders, including psychotic disorders andschizophrenia spectrum disorders such as schizotypal (personality)disorder, delusional disorder, brief psychotic disorder,schizophreniform disorder, schizophrenia, schizoaffective disorder,substance/medication-induced psychotic disorder, and psychotic disorderdue to another medical condition; bipolar disorders such as bipolar Idisorder, bipolar II disorder, cyclothymic disorder,substance/medication-induced bipolar and related disorder; depressivedisorders, such as disruptive mood dysregulation disorder, majordepressive disorder, single and recurrent episodes, persistentdepressive disorder (dysthymia), premenstrual dysphoric disorder,substance/medication-induced depressive disorder, and depressivedisorder due to another medical condition; anxiety disorders, such asseparation anxiety disorder, selective mutism, specific phobia, socialanxiety disorder (social phobia), panic disorder, agoraphobia,generalized anxiety disorder and the like;

Cardiovascular diseases such as heart failure, myocardiopathy, atrialfibrillation, pulmonary artery hypertension, hemorrhagic shock, stroke,ischemic heart disease, myocarditis and valvular disease; MuscleAtrophy; and Cachexia.

For the uses and methods of treatment described herein, any of thecompounds of the invention, including any of the embodiments thereof,may be used.

Accordingly, the invention further provides a compound of Formula (I),or pharmaceutically acceptable salt thereof, for use as a medicament.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment of adisease associated with HDAC6.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of a disease associated with HDAC6.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for treating adisease associated with HDAC6.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use as a HDAC6 inhibitor.

The present invention further provides a method for treating a diseaseassociated with HDAC6, comprising administering a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.

The present invention further provides a method of inhibiting HDAC6activity, comprising administering to a patient in need of saidtreatment an amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, sufficient to inhibit HDAC6 activity.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment of adisease selected from cancer, an autoimmune or inflammatory disease,transplant rejection, a ciliopathy, a disease of the nervous system, amental or behavioral disorder, an infectious disease, a cardiovasculardisease, muscle atrophy and cachexia.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of a disease selected from cancer, anautoimmune or inflammatory disease, transplant rejection, a ciliopathy,a disease of the nervous system, a mental or behavioral disorder, aninfectious disease, a cardiovascular disease, muscle atrophy andcachexia.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for treating adisease selected from cancer, an autoimmune or inflammatory disease,transplant rejection, a ciliopathy, a disease of the nervous system, amental or behavioral disorder, an infectious disease, a cardiovasculardisease, muscle atrophy and cachexia.

The present invention further provides a method for treating a diseaseselected from cancer, an autoimmune or inflammatory disease, transplantrejection, a ciliopathy, a disease of the nervous system, a mental orbehavioral disorder, an infectious disease, a cardiovascular disease,muscle atrophy and cachexia, comprising administering a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.

The present invention further provides a method of inhibiting HDAC6activity in a sample (e.g. a biological sample), comprising contactingsaid sample (e.g. said biological sample) with a compound of Formula(I), or pharmaceutically acceptable salt thereof.

The present invention further provides the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, as a HDAC6 inhibitorin research, particularly as a research tool compound for inhibitingHDAC6. Accordingly, the invention relates to the in vitro use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,as a HDAC6 inhibitor and, in particular, to the in vitro use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,as a research tool compound acting as a HDAC6 inhibitor. The inventionlikewise relates to a method, particularly an in vitro method, ofinhibiting HDAC6, the method comprising applying a compound of Formula(I), or a pharmaceutically acceptable salt thereof, to a sample (e.g., abiological sample). It is to be understood that the term “in vitro” isused in this specific context in the sense of “outside a living human oranimal body”, which includes, in particular, experiments performed withcells, cellular or subcellular extracts, and/or biological molecules inan artificial environment such as an aqueous solution or a culturemedium which may be provided, e.g., in a flask, a test tube, a Petridish, a microtiter plate, etc.

Unless otherwise stated, any description of a method of treatmentincludes use of the compounds to provide such treatment as is describedherein, as well as use of the compounds to prepare a medicament to treatsuch condition.

Any reference to a compound of Formula (I) herein includes a referenceto any of the compounds of Formula (IIa), (IIb), (IIIa), (IIIb), (IVa),(IVa-1), (IVb) and (IVb-1), and to any embodiments thereof as describedherein.

The term “disease associated HDAC6” and the like refer to any disease orcondition in which HDAC6 plays a role, and/or where the disease orcondition is associated with expression or activity of a HDAC6, and/ordiseases or conditions the course of which can be influenced bymodulating HDAC6. Diseases associated with HDAC6 include, withoutlimitation, the diseases and conditions as described herein. Preferably,the disease associated with HDAC is a disease selected from cancer, anautoimmune or inflammatory disease, transplant rejection, a ciliopathy,a disease of the nervous system, a mental or behavioral disorder, aninfectious disease, a cardiovascular disease, muscle atrophy andcachexia.

As used herein, the term “subject” or “patient” or “individual” refersto any animals, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans (e.g., a male human or a female human).

As used herein, the term “biological sample” includes, withoutlimitation, a cell, cell cultures or extracts thereof; biopsied materialobtained from an animal, e.g. a human, or extracts thereof; and blood,saliva, urine, feces, or any other body fluids or extracts thereof.

As used herein, the term “therapeutically effective amount” refers tothe amount of active compound that elicits the biological or medicinalresponse that is being sought in subject (preferably a human).Accordingly, a therapeutically effective amount of a compound may be anamount which is sufficient to treat a disease or disorder, delay theonset or progression of a disease or disorder, and/or alleviate one ormore symptoms of the disease or disorder, when administered to a subjectsuffering from said disease or disorder. The precise effective amountfor a subject will depend upon a variety of factors such as thesubject's body weight, size and health, the nature and extent of thecondition to be treated, and the therapeutic or combination oftherapeutics selected for administration. Therapeutically effectiveamounts for a given situation can be determined by routineexperimentation that is within the skill and judgement of the clinician.

For any compound, the therapeutically effective amount can be estimatedinitially either in in vitro assays, e.g. cell culture assays, or inanimal models, e.g. mice, rats or dogs. The animal model may also beused to determine the appropriate concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Therapeutic efficacy andtoxicity may be determined by standard procedures in cell cultures orexperimental animals, e.g. ED50 and LD50 values can be determined andthe ratio between toxic and therapeutic effects, also known astherapeutic index, may be calculated and used to determine suitabledoses for use in humans.

As used herein, unless otherwise stated, the term “treating” and“treatment” in relation to a disease, disorder or condition refers tothe management and care of a patient for the purpose of combating adisease, disorder or condition, such as to reverse, alleviate, inhibitthe process of, or prevent the disease, disorder or condition to whichsuch term applies, or one or more symptoms of such disease, disorder orcondition, and includes the administration of a compound of theinvention (or a pharmaceutically acceptable salt thereof) to prevent theonset of the symptoms or the complications, or alleviating the symptomsor complications, or eliminating the disease, condition or disorder.Preferably, treatment is curative or ameliorating.

While it is possible that a compound of the invention may beadministered for use in therapy directly as such, it is typicallyadministered in the form of a pharmaceutical composition. Thesecompositions comprise a compound of the invention (or a pharmaceuticallyacceptable salt thereof) as active pharmaceutical ingredient togetherwith one or more pharmaceutically acceptable carriers. For the purposesof the invention, a carrier is suitable for use in the pharmaceuticalcompositions described herein if it is compatible with the otheringredients of the composition and not deleterious to the recipient ofthe composition. A “pharmaceutically acceptable carrier” includesnon-API (API refers to Active Pharmaceutical Ingredient) substances,such as disintegrators, binders, fillers, lubricants and the like, usedin formulating pharmaceutical products and regarded as safe foradministering to subjects (particularly humans) according to establishedgovernmental standards, including those promulgated by the United StatesFood and Drug Administration and the European Medical Agency.Pharmaceutically acceptable carriers are well known to those skilled inthe art and are selected on the basis of the chosen type of formulationand route of administration, according to standard pharmaceuticalpractice as described for example in Remington: The Science and Practiceof Pharmacy 22nd edition, edited by Loyd V Allen Jr, PharmaceuticalPress, Philadelphia, 2012).

Accordingly, provided herein is a pharmaceutical composition comprisinga compound of Formula (I) (including any of its subgenus of Formula(IIa), (IIb), (IIIa), (IIIb), (IVa), (IVa-1), (IVb) and (IVb-1), and anyembodiments thereof as described herein), or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutical acceptablecarriers.

Pharmaceutical compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,for example via oral, parenteral, pulmonary or topical route. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal or intramuscular. Parenteral administration can be inthe form of a single bolus dose, or may be, for example, by a continuousperfusion pump. Pulmonary administration includes e.g. by inhalation orinsufflation of powders or aerosols, including by nebulizer. Topicaladministration includes transdermal, epidermal, ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery.

The compositions can be formulated as to provide quick (immediate),sustained or delayed release of the active ingredient afteradministration to the patient by using methods known in the art.

Examples of pharmaceutically acceptable excipients include lactose,dextrose, sucrose, sorbitol, mannitol, staches, gum acacia, calciumphosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, andmethyl cellulose. The pharmaceutical compositions can additionallyinclude further pharmaceutically acceptable excipients including:lubricating agents such as talc, magnesium stearate and mineral oil;wetting agents; emusifying and suspending agents; preserving agents suchas methyl- and propylhydroxybenzoates; sweetening agents; flavouringagents; and colouring agents.

Suitable oral dosage forms include, for examples, tablets, pills,sachets or capsules of hard or soft gelatin or any other suitablematerial. For example, the active compound can be incorporated into aformulation that includes pharmaceutically acceptable carriers such asbinders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g.,starch, lactose), lubricants (e.g., magnesium stearate, silicondioxide), disintegrating agents (e.g., alginate, Primogel, corn starch),and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin,methyl salicylate, and peppermint). They can then be compressed intotablets or enclosed in capsules using conventional techniques. Thecapsules and tablets can also be coated with various coatings known inthe art to modify the flavors, tastes, colors, and shapes of thecapsules and tablets. In addition, liquid carriers such as fatty oil canalso be included in capsules. Oral formulations can also be in the formof suspensions, solutions, syrups and the like. If desired, conventionalagents for modifying flavors, tastes, color and the like can be added.

Pharmaceutical compositions suitable for parenteral administrationinclude sterile aqueous solutions or suspensions, or can bealternatively prepared in lyophilized form for extemporaneouspreparation of a solution or suspension using a sterile aqueous carrierprior to use. In such formulations, diluents or pharmaceuticallyacceptable carriers such as sterile water and physiological salinebuffer can be used. Other conventional solvents, pH buffers,stabilizers, anti-bacterial agents, surfactants, and antioxidants canall be included. For example, useful components include sodium chloride,acetates, citrates or phosphates buffers, glycerin, dextrose, fixedoils, methyl parabens, polyethylene glycol, propylene glycol, sodiumbisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteralformulations can be stored in any conventional containers such as vialsand ampoules.

Compositions for administration by inhalation or insufflation includesolutions and suspensions in pharmaceutically acceptable aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidcompositions may include suitable pharmaceutically acceptable excipientsas described above. Such compositions may be administered by the oral ornasal respiratory route for local or systemic effect. Compositions canbe nebulized by use of a suitable gas. Nebulized solutions may bebreathed directly from the nebulizing device or the nebulizing devicemay be attached to a face mask or the breathing chamber. Solutions,suspensions and powder compositions can be administered orally ornasally from devices which deliver the formulation in an appropriatemanner.

Pharmaceutical compositions for topical administration may includetransdermal patches, ointments, lotions, creams, gels, drops,suppositories, sprays, liquids and powders. Topical formulations cancontain one or more conventional carriers. For example, ointments cancontain water and one or more hydrophobic carriers selected from liquidparaffin, polyoxyethylene alkyl ether, propylene glycol, white vaselineand the like. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components such ascetylstearyl alcohol, glycerin monostearate and the like. Gels can beformulated using isopropyl alcohol and water, suitably in combinationwith other excipients such as glycerol, hydroxyethyl cellulose and thelike.

The pharmaceutical compositions, like oral and parenteral compositions,can be formulated in unit dosage forms for ease of administration anduniformity of dosage. As used herein, “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for administrationto subjects, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect, inassociation with one or more suitable pharmaceutical carriers.

In therapeutic applications, pharmaceutical compositions are to beadministered in a manner appropriate to the disease to be treated, asdetermined by a person skilled in the medical arts. An appropriate doseand suitable duration and frequency of administration will be determinedby such factors as the condition of the patient, the type and severityof the disease, the particular form of the active ingredient, the methodof administration, among others. In general, an appropriate dose andadministration regimen provides the pharmaceutical composition in anamount sufficient to provide therapeutic benefit, for example animproved clinical outcome, such as more frequent complete or partialremissions, or longer disease-free and/or overall survival, or lesseningof symptoms severity, or any other objectively identifiable improvementas noted by the clinical. Effective doses may generally be assessed orextrapolated using experimental models like dose-response curves derivedfrom in vitro or animal model test systems.

The pharmaceutical compositions of the invention can be included in acontainer, pack or dispenser together with instructions foradministration.

The compounds of the invention can be administered as a single activeagent or may also be used or administered in combination with one ormore additional therapeutically active agents, e.g. drugs useful in thetreatment of a disease selected from cancers, autoimmune or inflammatorydiseases, transplant rejection, ciliopathies, diseases of the nervoussystem, mental or behavioral disorders, infectious diseases,cardiovascular diseases, muscle atrophy and cachexia. Combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of the invention and one or moreadditional therapeutically active agents, as well as administration ofthe compound of the invention and each additional therapeutically activeagent in its own separate pharmaceutical dosage formulation for separateadministration. If administered separately, the administration can besimultaneous, sequential or separate, and the compound of the inventionand the additional therapeutic agent(s) can be administered via the sameadministration route or using different administration routes, forexample one compound can be administered orally and the otherintravenously. Moreover, as explained above, the compounds of theinvention can also be used in monotherapy, particularly in themonotherapeutic treatment of a disease selected from cancer, anautoimmune or inflammatory disease, transplant rejection, a ciliopathy,a disease of the nervous system, a mental or behavioral disorder, aninfectious disease, a cardiovascular disease, muscle atrophy, andcachexia.

EXAMPLES

The following abbreviations have been used in the examples:

AcN: acetonitrileAcOH: acetic acidaq: aqueous,Boc: tert-butyloxycarbonyln-BuOH: n-butanol

DCM: Dichloromethane

DIAD: Diisopropyl azodicarboxylate

DIPEA: N,N-Diisopropylethylamine, DMF: N,N-dimethylformamide

EtOAc: ethyl acetateEtOH: ethanolFA: Formic acidHPLC: high performance liquid chromatographyLC-MS: liquid chromatography-mass spectroscopy

MeI: Iodomethane

MeOH: methanolPPh₃: triphenylphosphinePd(PPh₃)₄: tetrakis(triphenylphosphine) palladium (0)Pd(PPh₃)₂Cl₂: Bis(triphenylphosphine)palladium chloridePet ether: petroleum ether,pTSA: p-Toluenesulfonic acid monohydratert (or RT): room temperatureRt: retention time,TBAB: Tetrabutylammonium bromideTEA: triethylamineTFA: Trifluoroacetic acidTHF: tetrahydrofuraneTHP: tetrahydropyranT₃P: Propylphosphonic anhydride solution ≥50 wt. % in ethyl acetate

One of the following methods was used for the determination by LC-MS:

Method 1: Column: KINETEX-1.7 u XB-C18 100A (50 mm×2.1 mm, 1.7 μm);Mobile Phase: A: 0.05% Formic Acid in Water B: 0.05% Formic Acid inAcetonitrile; Gradient: Time/% A: 0/97, 0.3/97, 3.2/2, 4.8/2, 5/97,5.10/97 Column Temp: 35° C.; Flow Rate: 0.6 mL/minMethod 2: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: B: 0.1% Formic Acid in Water A: 0.1% Formic Acid in Acetonitrile;Gradient: Time/% B: 0/97, 0.3/97, 3.2/2, 4/2, 4.01/97; Column Temp: 35°C.; Flow Rate: 0.6 mL/min;Method 3: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: B: 0.1% Formic Acid in Water, A: 0.1% Formic Acid inAcetonitrile; Gradient: Time/% B: 0/97, 0.3/97, 3.0/2, 4.5/2, 4.51/97;Column Temp: 35° C.; Flow Rate: 0.6 mL/min.Method 4: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: B: 0.1% Formic Acid in Water A: 0.1% Formic Acid in Acetonitrile;Gradient: Time/% B: 0/97, 0.3/97, 2.2/2, 3.30/2, 4.5/2, 4.51/97; ColumnTemp: 35° C.; Flow Rate: 0.6 mL/min;Method 5: Column—AQUITY UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase-A: 0.1% FA in Water, B: 0.1% FA in Acetonitrile: T % A of: 0/90,1/10, 2.20/10, 2.30/90, 2.60./90Flow-0.8 mL/min, Temp: 50° C.Method 6: Column—AQUITY UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); Mobilephase-A: 0.1% FA in Water, B: 0.1% FA in Acetonitrile T % A of: 0/95,0.3/95, 2.0/5, 3.5/5, 3.6/95, 4.2/95Flow-0.6 mL/min, Temp: 40° C.Method 7: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: A: 0.05% Formic Acid in Acetonitrile, B: 0.05% Formic Acid inWater; Gradient: Time/% B: 0/97, 0.3/97, 3.2/2, 3.8/2, 4.3/97, 4.5/97;Column Temp: 35° C.; Flow Rate: 0.6 mL/minMethod 8: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: A; 0.1% Formic Acid in water, B: 0.1% Formic Acid inAcetonitrile; Gradient: Time/% B: 0/97, 0.3/97, 2.7/2, 3.5/2, 3.51/97,Column Temp: 35° C.; Flow Rate: 0.6 mL/min;Method 9: Column—AQUITY UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); Mobilephase-A: 0.1% FA in Water, B: 0.1% FA in Acetonitrile; T % A of: 0/97,0.3/97, 3.0/2, 4.0/2, 4.2/97, 4.50/97Flow-0.6 mL/min, Temp: 35° C.Method 10: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid inAcetonitrile; Gradient: Time/% A: 0/97, 0.3/97, 3.0/2, 4.0/2, 4.3/97,4.50/97; Column Temp: 35° C.; Flow Rate: 0.6 mL/minMethod 11: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid inAcetonitrile; Gradient: Time/% B: 0/5, 0.3/95, 2.0/95, 3.7/95, 4.2/5,5.7/5; Column Temp: 40° C.; Flow Rate: 0.5 mL/minMethod 12: Column—AQUITY UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); Mobilephase-A: 0.1% FA in Water, B: 0.1% FA in Acetonitrile; T % A of: 0/98,0.2/98, 1.8/2, 2.4/2, 2.60/98, 3.0/98. Flow-0.8 mL/min, Temp: 50°Method 13: Column: YMC TRAIT C18; Mobile Phase: A: Acetonitrile, B: 0.01M Ammonium Bicarbonate in Aq; Gradient: A=40%, B=60%. Flow Rate: 25.0mL/min.Method 14: Column: XBridge BEH C18 (50 mm×2.1 mm, 2.5 μm); Mobile Phase:A: 0.01 M Ammonium Formate in water; B: AcN; Gradient: Time/% B: 0/5,3/100, 3.5/100, 3.8/5, 4.3/5; Flow Rate: 0.7 mL/min. Temp: 40° C.Method 15: Column: XBridge BEH C18 (50 mm×3.0 mm, 2.5 μm); Mobile Phase:A: 0.01 M Ammonium Formate in water:AcN (95:5), B: 0.01 M AmmoniumFormate in water:AcN (5:95); Gradient: Time/% B: 0/2, 4/98, 4.5/98, 5/2,5.5/2, 6.5/2; Flow Rate: 1.0 mL/minMethod 16: Column: XBridge BEH C18 (50 mm×3.0 mm, 2.5 μm); Mobile Phase:A: 0.01 M Ammonium Formate in water:AcN (95:5), B: 0.01 M AmmoniumFormate in water:AcN (5:95); Gradient: Time/% B: 0/2, 2/2, 7/98, 7.5/98,8.5/2, 10/2; Flow Rate: 1.0 mL/min;Method 17: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: A: 0.01 M Ammonium Bicarbonate in Water, B: Acetonitrile;Gradient: Time/% B: 0/3; 1.0/3; 7.0/100; 7.5/100; 9.0/3; 10.0/3. ColumnTemp: 35° C.; Flow Rate: 0.5 mL/min;Method 18: Column: XBridge BEH C18 (50 mm×2.10 mm, 2.5 μm); MobilePhase: A: 0.01 M Ammonium Formate in water:AcN (95:5), B: Acetonitrile;Gradient: Time/% B: 0/5; 1.0/5; 7/100; 7.5/100; 9/5, 10/5. Column Temp:40° C.; Flow Rate: 0.7 mL/min;Method 19: Column: XBridge BEH C18 (50 mm×3.0 mm, 2.5 μm); Mobile PhaseA: 0.01 M Ammonium Formate in water:AcN (95:5), B: 0.01 M AmmoniumFormate in water:AcN (5:95); Gradient: Time/% B: 0/2, 1/2, 4/98, 4.5/98,5.5/2, 6.5/2; Flow Rate: 1.0 mL/min;Method 20: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid inAcetonitrile; Gradient: Time/% A: 0/97, 1.0/97, 7.0/0, 7.5/0, 9.0/97;Column Temp: 35° C.; Flow Rate: 0.5 mL/minMethod 21: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid inAcetonitrile; Gradient: Time/% A: 0/5, 0.1/5, 2.7/100, 3.5/100, 3.8/5;4.3/5 Column Temp: 40° C.; Flow Rate: 0.7 mL/minMethod 22: Column: XBridge BEH C18 (50 mm×2.1 mm, 2.5 μm); Mobile PhaseA: 0.01 M Ammonium Formate in water:AcN (95:5), B: 0.01 M AmmoniumFormate in water:AcN (5:95); Gradient: Time/% B: 0/2, 1/2, 7/100,7.5/100, 9/2, 10/2; Flow Rate: 0.7 mL/min;Method 23: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 2.5 μm); MobilePhase A: 0.01 M Ammonium Acetate in water; B: AcN; Gradient: Time/% B:0/5, 0.2/5, 7/100, 8/100, 8.5/5, 11/5; Column Temp: 40° C.; Flow Rate:0.5 mL/min;Method 24: Column: Luna Omega 3 μm PS C18 100A; Mobile Phase A: 0.01 MAmmonium Formate in water:AcN (95:5); B: 0.01 M Ammonium Formate inwater:AcN (5:95); Gradient: Time/% B: 0/2, 1/2, 4/98, 4.5/98, 5.5/2,6.5/2; Flow Rate: 1.0 mL/min;Method 25: Column—AQUITY UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); Mobilephase-A: 0.1% FA in Water, B: 0.1% FA in Acetonitrile T % A of: 0/95,0.3/95, 2.0/5, 3.5/5, 3.6/95, 4.4/95Flow-0.6 mL/min, Temp: 40° C.Method 26: Column: Aquity UPLC BEH C18 (50 mm×2.1 mm, 1.7 μm); MobilePhase A: 0.01 M Ammonium Acetate in water; B: AcN; Gradient: Time/% A:0/5, 0.1/5, 2.4/100, 3.8/100, 4.0/5; 4.5/5 Column Temp: 50° C.; FlowRate: 0.5 mL/minMethod 27: Column: Luna Omega 3 μm PS C18 100A); Mobile Phase A: 0.01 MAmmonium Formate in water: AcN (95:5), B: 0.01 M Ammonium Formate inwater:AcN (5:95); Gradient: Time/% B: 0/2, 1/2, 7/100, 7.5/100, 9/2,10/2; Flow Rate: 1.0 mL/min.

Reference Example 1 2-(Trimethylstannyl)isonicotinonitrile

To a stirred solution of 2-bromoisoniconitrile (2 g, 10.92 mmol) intoluene (20 mL), hexamethylditin (4.6 g, 14.20 mmol), and Pd(PPh₃)4 (1.2g, 1.09 mmol) were added at rt. The resulting solution was degassed withnitrogen for 10 min and heated to 110° C. for 16 h. The reaction mixturewas evaporated under reduced pressure and the crude compound waspurified by flash column chromatography on neutral alumina using 50%EtOAc in petroleum ether to afford the title compound (1.5 g, 51.7%).

LC-MS (method 1): R_(t)=1.93 min; m/z=269.08 (M+H⁺)

Reference Example 2 5-Bromo-1-butyl-1H-pyrrolo[2,3-c]pyridine

To a stirred suspension of 60% NaH (0.146 g, 6.091 mmol) in DMF (20 mL),5-bromo-1H-pyrrolo[2,3-c]pyridine (0.8 g, 4.06 mmol) was added at 0° C.and stirred for 15 min. Then, 1-bromo butane (0.66 g, 4.873 mmol) wasadded to the reaction mixture at 0° C. The resulting mixture was allowedto warm to rt and stirred for 16 h. The reaction mixture was quenchedwith water and extracted EtOAc and the organic layer was dried overanhydrous Na₂SO₄, and it was concentrated under reduced pressure. Thecrude compound was purified by flash column chromatography using 10%EtOAc in pet ether as an eluent to afford the title compound (0.78 g,67%).

LC-MS (method 2): R_(t)=2.27 min; m/z=253.17 (M+H⁺).

Following a similar procedure to that described in reference example 2,but using in each case the corresponding starting materials, thefollowing compounds were obtained:

Reference Starting HPLC R_(t) example Compound name material method(min) m/z 2a 5-Bromo-1-propyl- 1- 3 2.23 239.06 1H-pyrrolo lodopropane(M+H⁺) [2,3-c]pyridine 2b 5-Bromo-1-(2- 1-Bromo-2- 15 3.30 255.21methoxyethyl)-1H- methoxy (M+H⁺) pyrrolo[2,3-c] ethane pyridine (*) (*)0.02 eq of Nal were added.

Reference Example 35-Bromo-1-butyl-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamideStep a. 5-Bromo-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid (500 mg, 2.07 mmol) in DMF, dimethyl amine hydrochloride (168 mg,2.07 mmol), TEA (1.49 g, 10.37 mmol) and T₃P (1.97 g, 6.21 mmol) wereadded at 0° C. The resulting mixture was allowed to stir at rt for 16 h.The reaction mixture was diluted with water and extracted with EtOAc.The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The crude compound was purifiedby silica gel column chromatography and eluted at 5% MeOH in DCM toafford the title compound (450 mg, 78%).

LC-MS (method 4): R_(t)=1.75 min; m/z=270.15 (M+H⁺+2).

Step b.5-Bromo-1-butyl-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

To a stirred solution of the compound obtained in the previous section,step a (1.4 g, 5.24 mmol) in DMF, 60% NaH (1.04 g, 26.21 mmol) was addedat 0° C. The reaction mixture was stirred for 15 minutes at the sametemperature and then butyl iodide (1.92 g, 10.48 mmol) was added. Thesuspension was stirred at rt for 16 h. The reaction mixture was cooledat 0° C., quenched with water and extracted with EtOAc. The separatedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography and eluted at 5% MeOH in DCM to afford the titlecompound (1.0 g, 59.8%)

LC-MS (method 5): R_(t)=1.10 min; m/z=325.36 (M+H⁺).

Following a similar procedure to that described in reference example 3,but using in each case the corresponding starting material, thefollowing compounds were obtained:

Reference Starting HPLC R_(t) example Compound name material method(min) m/z 3a 5-Bromo-N,N,1- Dimethyl amine 6 1.62 282.10 trimethyl-hydrochloride (M+H⁺) 1H-pyrrolo[2,3-c] (step a) and pyridine-2-iodomethane carboxamide (step b) 3b 5-Bromo-1-butyl- Ethyl amine 6 2.12322.21 N-ethyl-1H-pyrrolo hydrochloride (M−H⁺) [2,3-c]pyridine- (step a)and 2-carboxamide butyl iodide 3c 5-Bromo-1-butyl- Diethyl amine 6 2.26352.28 N,N-diethyl- hydrochloride (M+H⁺) 1H-pyrrolo[2,3-c] (step a) andpyridine-2- butyl iodide carboxamide (step b)

Reference Example 43-((6-Bromopyridin-3-yl)oxy)-N,N-diethylpropan-1-amine

To a stirred solution of 6-bromopyridin-3-ol (5.0 g, 28.73 mmol) in THF(50 mL), PPh₃ (15.0 g, 57.47 mmol), DIAD (8.7 g, 43.10 mmol) and3-(diethylamino)propan-1-ol (5.64 g, 43.10 mmol) were added at 0° C. Thereaction mixture was allowed to stir at rt for 16 h. The reactionmixture was diluted with water (100 mL) and extracted with EtOAc (2×100mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated. The crude compound waspurified by flash column chromatography using 100-200 silica gel andeluted with 40% EtOAc/pet ether to afford the title compound (3.1 g,38%) as a gummy liquid. LC-MS (method 7): R_(t)=1.50 min; m/z=287.18(M+H⁺).

Reference Example 51-(5-Bromo-1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine

To a stirred solution of reference example 2 (500 mg, 1.97 mmol) inn-BuOH (20 mL), 37% formaldehyde aqueous solution (37%) (0.78 mL, 9.88mmol), and dimethyl amine hydrochloride (805 mg, 9.88 mmol) were added.The reaction mixture was stirred at 120° C. for 16 h and then it wascooled to rt. The organic solvent was evaporated under reduced pressureto get a residue that was diluted with 1N NaOH aqueous solution andextracted with 10% MeOH/DCM (2×50 mL). The crude residue was evaporatedto get a crude compound that was purified by column chromatography on230-400 silica with 85% EtOAc/pet ether along with 0.5 mL of TEA toafford 400 mg (65%) of the title compound as a gummy solid.

LC-MS (method 5): R_(t)=0.77 min; m/z=312.12 (M+H⁺+2).

Following a similar procedure to that described in reference example 5,but using in each case the corresponding starting materials, thefollowing compounds were obtained:

Reference Starting HPLC R_(t) example Compound name material method(min) m/z 5a 5-Bromo-3-(piperidin- Piperidine 6 1.46 336.241-ylmethyl)-1- and (M+H⁺) propyl-1H-pyrrolo reference [2,3-c]pyridineexample 2a 5b 4-((5-Bromo-1- Morpholine 6 1.35 338.21 propyl-1H-pyrroloand (M+H⁺) [2,3-c]pyridin-3-yl) reference methyl)morpholine example 2a5c 1-(5-Bromo-1-propyl- Dimethyl 6 1.33 296.20 1H-pyrrolo[2,3-c] amine(M+H⁺) pyridin-3-yl)-N,N- hydrochloride dimethylmethanamine andreference example 2a

Reference Example 62-Bromo-5-(3-(4,4-difluoropiperidin-1-yl)propoxy)pyridine Step a.2-Bromo-5-(3-chloropropoxy)pyridine

To a stirred solution of 6-bromopyridin-3-ol (3 g, 17.2 mmol) in DMF (50mL), K₂CO₃ (7.1 g, 51.6 mmol) was added and stirred at rt for 15minutes. It was cooled to 0° C. and 1-bromo-3-chloropropane (4 g, 25.8mmol) was added. The resulting mixture was stirred at rt for 16 h. Thereaction mixture was diluted with ice cold water and extracted withEtOAc (3×100 mL), washed with water (2×80 mL) and then brine (50 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (2.8 g,64%) as a yellow gummy liquid.

LC-MS (method 6): R_(t)=2.04 min; m/z=250.01 (M+H⁺).

Step b. 2-Bromo-5-(3-(4,4-difluoropiperidin-1-yl)propoxy)pyridine

To a solution of the compound obtained in the previous section, step a(2 g, 7.98 mmol) in acetonitrile, 4,4-difluoropiperidine hydrochloride(1.88 g, 11.97 mmol), K₂CO₃ (3.3 g, 23.95 mmol), and NaI (1.19 g, 7.98mmol) were added at rt. The resulting mixture was stirred at 70° C. for24 h and then it was cooled to rt. The reaction mixture was poured intoice water (30 mL) and extracted with EtOAc (2×80 mL): The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was washed with n-pentane and dried toafford 1.5 g (56%) of the title compound as a gummy liquid.

LC-MS (method 5): R_(t)=0.66 min; m/z=335.15 (M+H⁺).

Following a similar procedure to that described in reference example 6,but using the corresponding starting material, the following compoundwas obtained:

Refer- ence exam- Starting HPLC R_(t) ple Compound name material method(min) m/z 6a 4-(3-((6- Morpholine 6 1.17 301.11 Bromopyridin-3-yl)(M+H⁺) oxy)propyl)morpholine 6b 3-(6-Bromopyridin- Demethyl 15 1.77259.34 3-yloxy)-N,N- amine (M+H⁺) dimethylpropan- hydrochloride 1-amine6c 2-((3-((6- 2- 14 1.43 289.0 Bromopyridin-3-yl) (Methylamino) (M+H⁺)oxy)propyl)(methyl) ethanol amino)ethan-1-ol

Reference Example 7 N-(6-Bromopyridin-3-yl)-N-butyl-3-methoxypropanamideStep a. 6-Bromo-N-butylpyridin-3-amine (2) (C2134-130)

To a stirred solution of 6-bromopyridin-3-amine (10 g, 57 mmol) in MeOH(100 mL), butyraldehyde (4.9 g, 69.36 mmol) was added and stirred for 16h at rt. It was cooled to 0° C. and NaBH₃CN (7.2 g, 115.6 mmol) wasadded. The resulting mixture was stirred at rt for 16 h. The reactionmixture was poured into cold water (100 mL), extracted with EtOAc (2×200mL) and washed with brine solution (150 mL). The organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to get a crude compound that was purified by columnchromatography with 13% EtOAc/pet-ether to afford 7 g (52%) of the titlecompound.

LC-MS (method 4): R_(t)=2.31 min; m/z=229.16 (M+H⁺).

Step b. N-(6-Bromopyridin-3-yl)-N-butyl-3-methoxypropanamide

To a stirred solution of the compound obtained in the previous section,step a (1500 mg, 6.54 mmol, 1.0 equiv) in DCM, 3-methoxypropanoic acid(1020 mg, 9.84 mmol), TEA (3.30 g, 32.75 mmolv) and T₃P (8.3 g, 26.18mmol) were added at 0° C. The reaction mixture was allowed to stir at rtfor 16 h. The reaction mixture was diluted with water and extracted withEtOAc. The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography and eluted at 30% EtOAc inpet ether to afford (1450 mg, 70%) of the title compound. LC-MS (method10): R_(t)=2.40 min; m/z=315.12 (M+H⁺).

Reference Example 86-Bromo-N-(cyclopropylmethyl)-N-methylpyridin-3-amine

To a stirred solution of 6-bromo-N-methylpyridin-3-amine (1200 mg, 6.44mmol) in DMF, 60% NaH (1030 mg, 25.76 mmol) was added at 0° C. andstirred at rt for 15 minutes. It was cooled at 0° C., and(bromomethyl)cyclopropane (1738 mg, 12.88 mmol) was added. It wasallowed to stir at rt for 1 h. The reaction mixture was cooled to 0° C.,quenched with water and extracted with EtOAc. The separated organiclayer was washed with water and brine solution and dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by column chromatography and eluted at 15% EtOAcin pet ether to afford the title compound (1.0 g, 64.2%) as a yellowgummy; LC-MS (method 5): R_(t)=1.20 min; m/z=240.97 (M+H⁺).

Reference Example 9 Tert-butyl(6-bromopyridin-3-yl)(3-(diethylamino)propyl)carbamate Step a.3-Chloro-N,N-diethylpropan-1-amine hydrochloride

To a stirred solution 3-(diethylamino)propan-1-ol (1 g, 7.63 mmol) inDCM (10 mL) was added SOCl₂ (1.1 mL, 15.26 mmol) at 0° C. and theresulting mixture was stirred at rt for 3 h. The reaction wasconcentrated under reduced pressure to afford the title compound (1 g,88%).

Step b. Tert-butyl(6-bromopyridin-3-yl)(3-(diethylamino)propyl)carbamate

To a stirred suspension of 60% NaH (0.15 g, 6.598 mmol) in DMF (50 mL),a solution of tert-butyl (6-bromopyridin-3-yl)carbamate (1.2 g, 4.399mmol) in DMF (10 mL) at 0° C. was added. The resulting mixture wasstirred for 15 min, and then the compound obtained in the previoussection, step a, was added (0.785 g, 5.274 mmol) to the reaction mixtureat 0° C. The resulting mixture was stirred at rt for 16 h. The reactionmixture was quenched with ice cold water and extracted with EtOAc. Theorganic layer was concentrated under reduced pressure and the obtainedcrude compound was purified by flash column chromatography using 100%EtOAc as an eluent to obtain the title compound (0.9 g, 53) LC-MS(method 13): R_(t)=1.55 min; m/z=388.09 (M+H⁺+2).

Reference Example 106-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)propyl)-N-methylpyridin-3-amineStep a. Tert-butyl (6-bromopyridin-3-yl)(3-chloropropyl)carbamate

To a stirred solution of tert-butyl 6-bromopyridin-3-ylcarbamate (2.0 g,7.352 mmol) in DMF (20 mL), 60% NaH (0.529 g, 22.05 mmol) was added at0° C. and stirred at rt for 15 minutes. Then, 1-bromo-3-chloropropane(2.308 g, 14.705 mmol) was added and the resulting mixture was allowedto stir at rt for 16 h. The reaction mixture was cooled to 0° C.,quenched with ice-water and extracted with EtOAc. The organic layerswere washed with water and brine solution, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography and eluted at 8% EtOAc inpet ether to afford the title compound (2.0 g, LCMS-75%) as a browncolour gummy; LC-MS (method 5): R_(t)=1.31 min; m/z=349.20 (M+H⁺).

Step b Tert-butyl(6-bromopyridin-3-yl)(3-(4,4-difluoropiperidin-1-yl)propyl)carbamate

To a stirred solution of 4,4-difluoropiperidine hydrochloride (1.815 g,11.49 mmol) in AcN (30 mL), NaI (1.027 g, 6.896 mmol) and K₂CO₃ (2.379g, 17.24 mmol) were added. The reaction mixture was stirred for 10minutes, the compound obtained in the previous section, step a (2.0 g,5.747 mmol) was added and heated to 90° C. for 16 h. The reactionmixture was filtered through a celite pad and it was washed with 10%MeOH in DCM. The filtrated solution was concentrated under reducedpressure and the crude compound was purified by silica gel columnchromatography using 25% EtOAc in pet ether as eluent to afford thetitle compound (1.1 g, 44%) as an off-white solid;

LC-MS (method 5): R_(t)=0.86 min; m/z=434.35 (M+H⁺).

Step c. 6-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)propyl)pyridin-3-amine

To a stirred solution of the compound obtained in the previous section,step b (1.4 g, 3.22 mmol) in DCM (10 mL), TFA (3.0 ml) was added at 0°C. and it was allowed to stir at rt for 3 h. The reaction mixture wasconcentrated under reduced pressure. The crude residue was diluted withwater, basified to pH-8 using saturated NaHCO₃ aqueous solution andextracted with EtOAc. The organic layers were washed with water andbrine solution. The organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford the titlecompound (1.01 g, 94%) as an off white solid;

LC-MS (method 6): R_(t)=1.40 min; m/z=334.11 (M+H⁺).

Step d.6-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)propyl)-N-methylpyridin-3-amine

To a stirred solution of the compound obtained in the previous section,step c, (3.0 g, 9.0 mmol) in formic acid (40 mL), paraformaldehyde (2.70g, 90.09 mmol) was added and heated at 100° C. for 16 h. The reactionmixture was concentrated under reduced pressure: The crude residue wasdissolved in water and basified to pH˜8 using saturated NaHCO₃ aqueoussolution and extracted with EtOAc (3×50 mL). The separated organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure The crude compound was purified by silica gel columnchromatography and eluted at 20% EtOAc in pet ether to afford the titlecompound (2.5 g, 79%) as an off-white solid.

LC-MS (method 6): R_(t)=1.55 min; m/z=348.13 (M+H⁺).

Reference Example 113-(2-Bromopyrimidin-5-yloxy)-N,N-diethylpropan-1-amine Step a.2-Bromopyrimidin-5-ol

To a stirred solution of 2-chloropyrimidin-5-ol (2 g, 15.3 mmol) in AcOH(6 mL), HBr (47% aqueous solution) (6 mL) was added at 0° C. and it wasstirred at rt for 15 minutes. The resulting mixture was stirred at 100°C. for 24 h. The solvents were evaporated under vacuum and then pouredinto ice cold water and extracted with EtOAc (2×100 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to get a crude residue that was purified by columnchromatography on 100-200 silica with 30% of EtOAc/pet ether to affordthe title compound (1.5 g, 55%) as an off white solid.

LC-MS (method 6): R_(t)=0.94 min; m/z=175.03 (M+H⁺).

Step b. 2-Bromo-5-(3-chloropropoxy)pyrimidine

To a stirred solution of the compound obtained in the previous section,step a (1.5 g, 8.6 mmol) in DMF, K₂CO₃ (3.5 g, 25.8 mmol) and1-bromo-3-chloropropane (2) (2 g, 12.9 mmol) were added. The resultingmixture was stirred at rt overnight. The reaction mixture was dilutedwith water, extracted with EtOAc (2×100 mL). The organic layer was driedover Na₂SO₄, and evaporated under reduced pressure to afford 1.8 g (83%)of a crude compound that was used for the next step without any furtherpurification.

LC-MS (method 6): R_(t)=1.89 min; m/z=251.08 (M+H⁺).

Step c. 3-(2-Bromopyrimidin-5-yloxy)-N,N-diethylpropan-1-amine

To a stirred solution of the compound obtained in the previous section,step b (1.8 g, 7.2 mmol) in AcN, K₂CO₃ (2.9 g, 21.6 mmol) and NaI (1.07g, 7.2 mmol) were added. The resulting mixture was stirred at rt for 15minutes and diethyl amine hydrochloride (2.6 g, 36 mmol) was added atrt. It was stirred at 70° C. for 16 h. The reaction mixture was dilutedwith ice cold water and extracted with EtOAc (3×100 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford the title compound (1.2 g, 58%) as a browngummy liquid.

LC-MS (method 6): R_(t)=1.08 min; m/z=288.18 (M+H⁺).

Reference Example 12N¹-(6-Bromopyridin-3-yl)-N³,N³-diethyl-N¹-methylpropane-1,3-diamine Stepa. N¹-(6-Bromopyridin-3-yl)-N³,N³-diethylpropane-1,3-diamine

To a stirred solution of reference example 9 (1.2 g, 3.1 mmol) in DCM(20 ml), TFA (3.5 ml) was added and allowed to stir at rt for 8 h. Thereaction mixture was concentrated to dryness to get a crude residue thatwas purified by column chromatography and eluted at 10% MeOH/DCM toafford 0.9 g (100%) of the title compound.

LC-MS (method 6): R_(t)=1.27 min; m/z=286.13 (M+H⁺).

Step b.N¹-(6-Bromopyridin-3-yl)-N³,N³-diethyl-N¹-methylpropane-1,3-diamine

To a stirred solution of the compound obtained in the previous section,step a (800 mg, 2.795 mmol) in formic acid (10 mL), paraformaldehyde(839 mg, 27.95 mmol) at 0° C. was added slowly and allowed to stir at95° C. for 16 h. The reaction mixture was concentrated under reducedpressure and the residue was dissolved in water. The aqueous layer wasbasified using saturated NaOH aqueous solution, and concentrated underreduced pressure. The obtained crude residue was purified by columnchromatography and eluted at 10% MeOH/DCM to afford the title compound(700 mg, 67.3%).

LC-MS (method 6): R_(t)=1.37 min; m/z=300.16 (M+H⁺).

REFERENCE 13 3-(6-Bromopyridin-3-yloxy)-N-methylpropan-1-amine

In a sealed tube, to a stirred solution of the compound obtained inreference example 6, step a (1 g, 4 mmol) in AcN, K₂CO₃ (1.6 g, 12 mmol)and NaI (300 mg, 2 mmol) were added at 0° C. and stirred at rt for 15minutes. Then, a solution of 33% methylamine in EtOH, (0.6 mL, 6 mmol)was added at 0° C. The resulting mixture was stirred at 60° C. for 16 h.It was was diluted with ice cold water and extracted with EtOAc. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to get a crude residue that was purified bycolumn chromatography on 230-400 silica with 2% MeOH/DCM as eluent toafford the title compound (750 mg, 76%) as a gummy liquid.

LC-MS (method 14): R_(t)=1.07 min; m/z=245.01 (M+H⁺).

REFERENCE 146-Bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridine

To a stirred solution of 6-bromo-1H-pyrrolo[3,2-c]pyridine (1 g, 3.36mmol) in DMF (20 mL), tetrahydro-2H-pyran-4-yl methanesulfonate (1.51 g,8.38 mmol), and Cs₂CO₃ (5.46 g, 16.8 mmol) were added at 0° C. Theresulting mixture was stirred at 100° C. for 16 h. The reaction mixturewas diluted with EtOAc and washed with water. The the organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrate under reducedpressure. The crude residue was purified by column chromatography andeluted at 10% MeOH in DCM to afford the title compound (0.33 g, 35%) asan off white solid.

LC-MS (method 6): R_(t)=1.73 min; m/z=281.07 (M+H⁺).

Following a similar procedure to that described in reference example 14,but using in the corresponding starting material, the following compoundwas obtained:

Reference Compound Starting HPLC R_(t) example name material method(min) m/z 14a 6-Bromo-1- (Tetrahydro-2H- 14 2.05 295.0 ((tetrahydro-pyran-4-yl) 2H-pyran-4-yl) methyl (M+H+) methyl)- methanesulfonate1H-pyrrolo [3,2-c]pyridine

Reference Example 153-((6-Bromopyridin-3-yl)oxy)-N-ethyl-N-phenethylpropan-1-amine Step a.3-((6-Bromopyridin-3-yl)oxy)propan-1-ol

To a stirred suspension of 6-bromopyridin-3-ol (5.0, 28.73 mmol) in DMF(40 mL), K₂CO₃ (11.90 g, 86.20 mmol) and 3-bromopropanol (4.39 g, 31.60mmol) were added at rt and stirred for 16 h. The reaction mixture wasquenched with ice cold water (150 mL) and extracted with ethyl acetate(2×60 mL). The combined organic layers were washed with water (100 mL)followed by brine solution (100 mL) and dried over anhydrous Na₂SO₄ andfiltered. The solution filtrated was concentrated under reduced pressureand the resulting crude compound was purified by flash columnchromatography using 30% of ethyl acetate in pet ether as the eluent toafford the title compound (3.50 g, 53%) as color less liquid.

LC-MS (method 5): R_(t)=0.82 min; m/z=232.05 (M+H⁺).

Step b. 2-Bromo-5-(3-bromopropoxy)pyridine

To a solution of the compound obtained in the previous section, step a,(3.50 g, 15.08 mmol) in DCM (50 mL), PPh₃ (11.0 g, 30.17 mmol) and CBr₄(9.98 g, 30.17 mmol) were added at 0° C. The resulting mixture wasstirred at room temperature for 6 h. The solvent was removed underreduced pressure and the crude residue was purified by silica gel columnusing 10% EtOAc in pet ether as an eluent to afford the title compound(2.50 g, 56%) as color less liquid.

LC-MS (method 5): R_(t)=1.19 min; m/z=293.99 (M+H⁺).

Step c. 3-((6-Bromopyridin-3-yl)oxy)-N-phenethylpropan-1-amine

To a solution of the compound obtained in the previous section, step b,(2.50 g, 8.47 mmol) and 2-phenylethanamine (1.54 g, 12.71 mmol) in AcN(50 mL), NaI (1.27 g, 8.47 mmol) and K₂CO₃ (3.50 g, 25.42 mmol) wereadded. The resulting mixture was heated at 60° C. for 16 h. The reactionmixture was tempered, filtered and the filtrate was concentrated underreduced pressure: The crude residue was purified by grace reverse phasecolumn chromatography using 35% AcN in 0.1% aq formic acid as eluent toafford the title compound (1.50 g, 53%) as color less liquid.

LC-MS (method 5): R_(t)=0.81 min; m/z=335.20 (M+H⁺).

Step d. 3-((6-Bromopyridin-3-yl)oxy)-N-ethyl-N-phenethylpropan-1-amine

To a solution of the compound obtained in the previous section, step c,(1.50 g, 4.47 mmol) in DMF (20 mL), K₂CO₃ (1.85 g, 13.43 mmol) and ethyliodide (1.04 g, 6.71 mmol) were added and stirred at room temperaturefor 16 h. The reaction mixture was quenched with ice cold water (150 mL)and extracted with ethyl acetate (2×60 mL). The combined organic layerswere washed with water (100 mL) followed by brine solution (100 mL) anddried over anhydrous Na₂SO₄ and filtered. The solution filtrated wasconcentrated under reduced pressure and the resulting crude compound waspurified by grace reverse phase column using 40% of Acetonirile in 0.1%aq. Formic acid an eluent to afford the title compound (1.10 g, 68%) ascolor less liquid. LC-MS (method 6): R_(t)=1.62 min; m/z=363.29 (M+H⁺).

Reference Example 16 N-(6-Bromopyridin-3-yl)-2-phenylacetamide

To a stirred solution of 6-bromopyridin-3-amine (2.0 g, 11.56 mmol) inDCM (50 mL), 2-phenylacetic acid (2.04 g, 15.02 mmol), and TEA (4.60 g,46.24 mmol) were added, followed by the addition of T₃P (9.19 g, 28.90mmol) at 0° C. The resulting mixture was stirred at rt for 16 h. Thereaction mixture was washed with saturated NaHCO₃ aqueous solution (100mL). The organic layer was dried over anhydrous Na₂SO₄ and filtered. Thefiltered solution was concentrated under reduced pressure and theresulting crude compound was purified by flash column chromatographyusing 25% ethyl acetate in pet ether as eluent to afford the titlecompound (2.30 g, 68%) as an off-white solid.

LC-MS (method 1): R_(t)=2.46 min; m/z=291.08 (M+H⁺).

Following a similar procedure to that described in reference example 16,but using in each case the corresponding starting material, thefollowing compound were obtained:

Reference HPLC R_(t) example Compound name Starting material method(min) m/z 16a N-(6-Bromopyridin-3-yl) 1-Methylpiperidine-4- 2 1.04300.15 -1-methylpiperidine- carboxylic (M+H+) 4-carboxamide acid and6-bromopyridin- 3-amine 16b N-(2-Bromopyridin- 2-Cyclobutylacetic 6 1.99269.10 4-yl)-2- acid and 6- (M+H+) cyclobutylacetamide bromopyridin4-amine 16c Tert-butyl 3-(2- 2-Bromoisonicotinic 6 2.18 384.29bromoisonicotinamido) acid and tert-butyl (M+H+) piperidi3-aminopiperidine- ne-1-carboxylate (*) 1-carboxylate 16d 2-Bromo-N-((1-2-Bromoisonicotinic 6 1.28 312.25 methylpiperidin4- acid I and (1-(M+H+) yl)methyl) methylpiperidin-4- isonicotinamide yl)methanamine 16e6-Bromo-N-((1- 6-Bromonicotinic 19 1.89 312.33 methylpiperidin-4- acidand (1- yl)methyl) methylpiperidin-4- nicotinamide (**) yl)methanamine(*) using THF instead of DCM. (**) using DMF instead of DCM

Reference Example 172-Bromo-4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)pyridine Step a.2-((2-Bromopyridin-4-yl)oxy)ethan-1-ol

To a stirred solution of 2-bromopyridin-4-ol (2.0 g, 11.5 mmol) in DMF,K₂CO₃ (3.96 g, 28.75 mmol) was added at rt. 2-Bromoethanol (2.15 g,17.25 mmol) was added slowly at 0° C. Then it was stirred at 70° C. for12 h. The reaction mixture was quenched with ice cold water andextracted with DCM. The organic layer was washed with saturated NaHCO₃aqueous solution, followed by brine solution and dried over anhydrousNa₂SO₄ and filtered. The filtered solution was concentrated underreduced pressure and the resulting crude compound was purified by flashcolumn chromatography (100-200) silica gel using 20% EtOAc/Pet ether asa eluent to afford the title compound (1.2 g, 47.8%) as a pale yellowliquid.

LC-MS (method 14): R_(t)=1.26 min; m/z=220.0 (M+H⁺+2).

Step b. 2-Bromo-4-(2-bromoethoxy)pyridine

To a stirred solution of the compound obtained in the previous section,step a (1.1 g, 5.0 mmol) in DCM, PPh₃ (1.57 g, 1.2 eq) and CBr₄ (3.31 g,10 mmol) were added at 0° C. It was stirred at rt for 12 h. The reactionmixture was quenched with ice cold water and extracted with DCM. Theorganic layer was washed with saturated NaHCO₃ aqueous solution,followed by brine solution and dried over anhydrous Na₂SO₄ and filtered.The solution filtrated was concentrated under reduced pressure and theresulting crude compound was purified by flash column chromatography(230-400) silica gel using 10% EtOAc/Pet ether as a eluent to afford thetitle compound (0.9 g, 64%) as a pale yellow liquid.

LC-MS (method 14): R_(t)=2.18 min; m/z=281.9 (M+H⁺).

Step c. 2-Bromo-4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)pyridine

To a stirred solution of the compound obtained in the previous section,step b (400 mg, 1.42 mmol) in AcN, K₂CO₃ (0.58 g, 4.26 mmol), NaI (0.1g, 0.71 mmol) and difluoropiperidine hydrochloride (0.25 g, 2.13 mmol)were added at rt and then heated at 80° C. for 12 h. Organic solventswere evaporated to dryness. The obtained crude residue was dissolved inwater and DCM. The combined organic layers were washed with waterfollowed by brine solution and dried over anhydrous Na₂SO₄ and filtered.The filtered solution was concentrated under reduced pressure and theresulting crude compound was purified by flash column chromatography(230-400) silica gel using 50% EtOAc/Pet ether as a eluent to afford thetitle compound (0.350 g, 76.7%) as a pale yellow liquid.

LC-MS (method 15): R_(t)=2.91 min; m/z=321.30 (M+H⁺).

Following a similar procedure to that described in reference example 17,but using the corresponding starting material, the following compoundwas obtained:

Reference Compound Starting HPLC R_(t) example name material method(min) m/z 17a 4-(2-((2- Morpholine 14 1.45 r289.0 Bromopyridin- (M+H⁺+2)4yl)oxy)ethyl) morpholine

Reference Example 184-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a stirred solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 10.3mmol) in DMF (30 mL), (2-(chloromethoxy)ethyl)trimethylsilane (2 g, 12.3mmol), and Cs₂CO₃ (10 g, 30.9 mmol) were added. The resulting mixturewas stirred at rt for 3 h. Solvents were evaporated and the cruderesidue was diluted with ice cold water and extracted with EtOAc. Thecombined organic layers were dried over anhydrous Na₂SO₄ and filtered.The filtered solution was concentrated under reduced pressure and theresulting crude compound was purified by flash column chromatographyusing 20-30% EtOAc/Pet ether to get the title compound (1.5 g, 44%) aspale yellow gummy.

LC-MS (method 14): R_(t)=3.08 min; m/z=325.2 (M+H⁺).

Reference Example 195-Bromo-1-propyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridineStep a. 5-Bromo-3-iodo-1H-pyrrolo[2,3-c]pyridine

To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (1 g, 5.1mmol) in DMF, KOH (0.86 g, 15.3 mmol) was added. It was stirred at rtfor 20 minutes and then, iodine (1.54 g, 6.12 mmol) was added. Theresulting mixture was stirred at rt for 16 h. The reaction mixture wasevaporated under vacuum to get a crude residue. Crushed ice was added tothe obtained crude residue and the precipitated solid was filtered,dried, and washed with diethylether to get 1 g (60%) of a crude compoundthat was used for the next step without any further purification.

LC-MS (method 6): R_(t)=1.94 min; m/z=323.01 (M+H⁺).

Step b. 5-Bromo-3-iodo-1-propyl-1H-pyrrolo[2,3-c]pyridine

To a stirred solution of the compound obtained in the previous section,step a (1 g, 3.1 mmol) in DMF, NaH (60%) (0.371 g, 9.2 mmol) was addedat 0° C. After 15 minutes, bromopropane (0.45 g, 3.72 mmol) was addedslowly and stirred at rt for 3 h. To the reaction mixture, crushed icewas added, and the precipitated solid was filtered, dried, and washedwith diethyl ether and n-pentane to get 900 mg (79%) of a crude compoundthat was used for the next step without any further purification.

LC-MS (method 6): R_(t)=2.28 min; m/z=365.01 (M+H⁺).

Step c.5-Bromo-1-propyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridine

To a stirred solution of the compound obtained in the previous section,step b (500 mg, 1.4 mmol) in) in a DMF/water 1:1 mixture, referenceexample 18 (0.545 g, 1.7 mmol), and Cs₂CO₃ (1.36 g, 4.2 mmol) wereadded. The resulting solution was degassed with nitrogen for 15 minutes,then PdCl₂ dppf (0.1 g, 0.14 mmol) was added and stirred at 90° C. for16 h. The reaction mixture was evaporated under vacuum to get a cruderesidue that was diluted with cold water and extracted with EtOAc. Thecombined organic layers were dried over anhydrous Na₂SO₄ and filtered.The filtered solution was concentrated under reduced pressure and theresulting crude compound was purified by flash column chromatographyusing 20-30% EtOAc/Pet ether to get the title compound (380 mg, 63%) aspale brown gummy.

LC-MS (method 6): R_(t)=2.39 min; m/z=435.34 (M+H⁺).

Following a similar procedure to that described in reference example 19,but using the corresponding starting material, the following compoundwas obtained:

Refer- ence exam- Compound Starting HPLC R_(t) ple name material method(min) m/z 19a 5-Bromo-1- Iodomethane 6 2.25 407.32 methyl-3-(1-((2-(M+H⁺). (trimethylsilyl) ethoxy) methyl)-1H- pyrazol-4-yl)- 1H-pyrrolo[2,3-c]pyridine 19b 5-Bromo-1-(2- 1-Bromo-2- 6 2.27 451.31methoxyethyl)- methoxyethane (M+H⁺). 3-(1-((2- (trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4- yl)-1H-pyrrolo [2,3-c]pyridine

Reference Example 20N-(2-Bromopyridin-4-yl)-2-(4,4-difluoropiperidin-1-yl)acetamide Step a.N-(2-Bromopyridin-4-yl)-2-chloroacetamide

To a stirred solution of 2-bromopyridin-4-amine (2 g, 11.5 mmol) in DCM(40 mL), DIPEA (4 mL, 23 mmol) and chloroacetyl chloride (1.85 mL, 23mmol) were added at 0° C. It was stirred at it for 3 h. The reactionmixture was diluted with EtOAc and washed with water. The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by column chromatography andeluted at 20% EtOAc in pet ether to afford the title compound (2.2 g,76.5%) as an off yellow solid.

LC-MS (method 6): R_(t)=1.70 min; m/z=249.02 (M+H⁺).

Step b. N-(2-Bromopyridin-4-yl)-2-(4,4-difluoropiperidin-1-yl)acetamide

To a stirred solution of the compound obtained in the previous section,step a (2.1 g, 8.4 mmol) in AcN (50 mL), K₂CO₃ (3.5 g, 25.2 mmol), NaI(1.62 g, 10.9 mmol), and 4, 4-difluoropiperidine hydrochloride (1.52 g,12.6 mmol) were added at 0° C. It was stirred at rt for 16 h. Thereaction mixture was filtered through a celite pad and washed with EtOAc(50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford a crude compound that wasused for the next step without any further purification (1.5 g, 53.4%)

LC-MS (method 6): R_(t)=1.42 min; m/z=336.16 (M+H⁺30 2).

Reference Example 212-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)ethyl)pyridin-4-amine

To a stirred solution of reference example 20 (1.0 g, 2.97 mmol) in THF(40 mL), LiAlH₄ (0.135 g, 3.56 mmol) was added at 0° C. It was stirredat rt for 3 h. The reaction mixture was poured into crushed ice waterand diluted with EtOAc. The resulting mixture was filtered through acelite pad and concentrated under reduced pressure to afford a crudecompound that was used for the next step without any furtherpurification (0.5 g, 52.6%) LC-MS (method 19): R_(t)=3.44 min;m/z=320.31 (M+H⁺).

Reference Example 225-Bromo-3-(piperidin-1-ylmethyl)-1H-pyrazolo[3,4-c]pyridine

Following a similar procedure to that described in reference example 5,but using 5-bromo-1H-pyrazolo[3,4-c]pyridine instead of referenceexample 2, the desired compound was obtained.

LC-MS (method 6): R_(t)=1.12 min; m/z=295.18 (M+H⁺).

Reference Example 236-Bromo-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridineStep a. 6-Bromo-1-(2-bromoethyl)-1H-pyrrolo[3,2-c]pyridine

To a stirred 40% NaOH aqueous solution (15 mL),6-bromo-1H-pyrrolo[3,2-c]pyridine (1 g, 5.07 mmol), TBAB (163 mg, 0.50mmol) and 1,2-dibromoethane (15 mL) were added. The resulting mixturewas stirred at 80° C. for 12 h. The reaction mixture was quenched withwater and extracted EtOAc. The organic layer was dried over anhydrousNa₂SO₄, concentrated under reduced pressure to get a crude compound thatwas used for the next step without any further purification (1.8 g).

LC-MS (method 6): R_(t)=1.77 min; m/z=304.80 (M+H⁺).

Step b.6-Bromo-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridine

To a stirred solution of the compound obtained in the previous section,step a (1 g, 3.2 mmol) in AcN (50 mL) was added 4,4-difluoropiperidinehydrochloride (780 mg, 5 mmol), K₂CO₃ (1.3 g, 9.6 mmol). The resultingsuspension was stirred at 70° C. for 16 h. The reaction mixture waspoured into cold water and extracted with EtOAc (2×80 mL). The organiclayer was dried and concentrated to get a crude compound that waspurified by flash column chromatography in 230-400 silica gel 28%EtOAc/pet ether as an eluent to afford the title compound (650 mg, 59%)as an off white solid.

LC-MS (method 6): R_(t)=1.26 min; m/z=344.26 (M+H⁺).

Reference Example 24 N-(2-Bromopyridin-4-yl)-3-phenylpropanamide

To a stirred solution of 2-bromopyridin-4-amine (500 mg, 2.9 mmol) inTHF (20 mL), 3-phenylpropanoyl chloride (585 mg, 3.5 mmol) and DIPEA(1.5 mL, 8.7 mmol) were added and it was stirred at rt for 16 h. Thereaction mixture was poured to into ice water (50 ml) and extracted withEtOAc (2×100 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered to obtain a crude residue that was triturated in n-pentane anddried to afford the title compound (880, 36%) as a gummy solid.

LC-MS (method 14): R_(t)=2.27 min; m/z=305.0 (M+H⁺).

Reference Example 256-Bromo-1-(pyridin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridine

To a stirred solution of 6-bromo-1H-pyrrolo[3,2-c]pyridine (1 g, 5.07mmol) in DMF (25 mL), Cs₂CO₃ (4.95 g, 15.21 mmol) and4-(bromomethyl)pyridine hydrobromide (1.92 g, 7.60 mmol) were added. Theresulting suspension was allowed to stir at rt, and then heated to 50°C. for 16 h. The reaction mixture was poured into ice water andextracted with EtOAc (2×120 mL). The organic layer was washed with waterand brine solution, dried over anhydrous Na₂SO₄, and filtered. Theresulting solution was concentrated under reduced pressure to get acrude residue that was purified by flash column chromatography in230-400 silica gel 70% EtOAc/pet ether as an eluent to afford the titlecompound (800 mg, 57.7%) of the title compound as a light brown solid.LC-MS (method 15): R_(t)=2.33 min; m/z=288.27 (M+H⁺).

Following a similar procedure to that described in reference example 25,but using in each case the corresponding starting materials, thefollowing compounds were obtained:

Refer- ence exam- Compound Starting HPLC R_(t) ple name material method(min) m/z 25a 6-Bromo-1-(2- 6-Bromo-1H- 6 1.50 255.0 methoxyethyl)-pyrrolo[3,2-c] (M+H⁺) 1H-pyrrolo pyridine [3,2-c]pyridine and 1-bromo-2-methoxyethane 25b 6-Bromo- 6-Bromo-1H- 21 1.26 288.0 1-(pyridin-pyrrolo[3,2-c] (M+H⁺) 3-ylmethyl)- pyridine 1H-pyrrolo and 3-[3,2-c]pyridine (bromomethyl) pyridine 25c 6-Bromo-1- 6-Bromo-1H- 6 1.56287.9 (pyridin-2- pyrrolo[3,2-c] (M+H⁺) ylmethyl)- pyridine and 2-1H-pyrrolo (bromomethyl) [3,2-c]pyridine pyridine hydrobromide 25d5-Bromo-1-(2- 5-Bromo-1H- 19 3.28 256.2 methoxyethyl)- pyrazolo[3,4-(M+H⁺) 1H-pyrazolo c]pyridine and 1- bromo-2- [3,4-c]pyridinemethoxyethane 25e 5-Bromo-2-(2- 5-Bromo-1H- 19 3.08 256.2 methoxyethyl)-pyrazolo[3,4- (M+H⁺) 2H-pyrazolo c]pyridine and 1- [3,4-c]pyridinebromo-2- methoxyethane 25f 6-Bromo-1-((1- 6-Bromo-1H- 6 1.51 291.10methyl-1H- pyrrolo[3,2-c] (M+H⁺) pyrazol-4-yl) pyridine and methyl)-1H-4-(chloromethyl)- pyrrolo[3,2-c] 1-methyl- pyridine 1H-pyrazole

Reference Example 263-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

To a stirred solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg,1.01 mmol) in DMF (5 mL), 3,4-dihydro-2H-pyran (127 mg, 1.51 mmol) and acatalytic amount of pTSA were added at rt. The resulting solution wasstirred at 85° C. for 24 h. The reaction was cooled to rt, diluted withwater and extracted with EtOAc. The organic layer was washed with waterand brine solution, dried over anhydrous Na₂SO₄, and filtered. Theresulting solution was concentrated under reduced pressure to get crudea residue that was purified by flash columnchromatography to afford thetitle compound (150 mg, 52.8%).

LC-MS (method 1): R_(t)=2.24 min; m/z=282.30 (M+H⁺).

Reference Example 27 5-(3-(1H-Pyrazol-1-yl)propoxy)-2-bromopyridine

To a stirred solution of 1H-pyrazole (378 mg, 5.55 mmol) in) in DMF (10mL), 60% NaH (666 mg, 16.6 mmol) was added at 0° C. and it was stirredat rt for 15 min. Then, the compound obtained in reference example 6,section a, (1.25 g, 6.1 mmol) was added (slowly). It was stirred at rtfor 3 h. It was purified by silica gel column chromatography using using30-80% EtOAc/Pet ether to afford the title compound (1.2 g, 70%) asoff-white solid.

LC-MS (method 14): R_(t)=2.09 min; m/z=282.0 (M+H⁺).

Reference Example 286-Bromo-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridineStep a. Tert-butyl4-(6-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate in DMF (30 mL), Cs₂CO₃(3.08 g. 9.5 mmol) and 6-bromo-1H-pyrrolo[3,2-c]pyridine (372 mg, 1.9mmol) were added at rt. The reaction mixture was stirred at 90° C. for12 h. The reaction mixture was quenched with ice water and extractedwith DCM. The organic layer was dried over anhydrous Na₂SO₄, and it wasconcentrated under reduced pressure. The crude compound was purified byflash column chromatography using 20% EtOAc in pet ether as an eluent toafford the title compound (0.60 g, 44%).

LC-MS (method 14): R_(t)=2.65 min; m/z=380.0 (M+H⁺).

Step b. 6-Bromo-1-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridinehydrochloride

To a stirred solution the compound obtained in the previous section,step a, (0.6 g, 1.6 mmol) in dioxane (25 mL), 4M HCl in dioxane (0.2 mL)was added. The resulting mixture was stirred at rt for 3 h. Organicsolvents were removed under vaccum, and the crude residue was trituratedwith dietjyl ether. It was filtered under reduced pressure to afford 400mg (89%) of the title compound

LC-MS (method 14): R_(t)=1.23 min; m/z=280.0 (M+H⁺).

Step c.6-Bromo-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine

To a stirred solution the compound obtained in the previous section,step b, (200 mg, 0.7 mmol) in acetone (15 ml), K₂CO₃ (0.483 mg, 3.5mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (450 mg, 1.4mmol) were added at rt. It was stirred at 55° C. overnight. Organicsolvents were removed under vacuum. The crude residue was extracted withDCM/water. Then combined organic layer was concentrated under reducedpressure to afford the title compound (150 mg. 58%) as an off whitesolid.

LC-MS (method 6): R_(t)=2.07 min; m/z=362.24 (M+H⁺).

Reference Example 295-Bromo-1-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridineStep a.5-Bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine

To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (1.0 g, 5.07mmol) in MeOH (20 mL), powder KOH (1.13 g, 20.28 mmol) was added. Theresulting mixture was stirred at rt for 10 minutes. Then,1-methylpiperidin-4-one (1.14 g, 10.14 mmol) was added and it wasrefluxed for 16 h. The reaction mixture was quenched with water andextracted with 10% MeOH in DMC. The separated organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto afford 800 mg (54%) of the title compound.

LC-MS (method 6): R_(t)=0.95 min; m/z=290.20 (M−H⁺).

Step b.5-Bromo-1-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine

To a stirred solution the compound obtained in the previous section,step a (800 mg, 2.74 mmol) in DMF (10 mL), NaH (60%) (325 mg, 8.22 mmol)were added at 0° C. and it was stirred for 15 min. Then, idobutane (1.0g, 5.48 mmol) was added and reaction mixture was stirred at rt for 16 h.The reaction mixture was quenched with water and extracted with EtOAcand the organic layer was dried over anhydrous Na₂SO₄, and it wasconcentrated under reduced pressure. The crude compound was purified byflash column chromatography using 25-30% EtOAc in pet ether as an eluentto afford the title compound (400 mg, 42%).

LC-MS (method 6): R_(t)=1.66 min; m/z=348.29 (M+H⁺).

Reference Example 30N,N-Dimethyl-3-(6-(trimethylstannyl)pyridin-3-yloxy)propan-1-amine)

To a stirred solution of reference example 6b (500 mg, 1.92 mmol) intoluene (20 mL), hexamethylditin (695 mg, 2.12 mmol), and Pd(PPh₃)₄ (223mg, 0.192 mmol) were added at rt. The resulting solution was degassedwith nitrogen for 10 min and heated to 110° C. for 16 h. The reactionmixture was evaporated under reduced pressure and the crude compound waspurified by flash column chromatography on neutral alumina using 10%EtOAc in petroleum ether to afford the title compound (390 mg, 58%).

LC-MS (method 21): R_(t)=2.02 min; m/z=345.0 (M+H⁺)

Reference Example 313-(2-Bromopyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole Step a.2-Bromo-N-hydroxyisonicotinimidamide

To a stirred solution of 2-bromoisonicotinonitrile (3 g, 16.4 mmol) inEtOH/MeOH (1:1) (50 mL), a 50% solution of NH₂OH.HCl (2.2 g, 32.8 mmol)in NaHCO₃ (2.7 g, 32.8 mmol) was added. The resulting solution washeated to 60° C., for 3 h. The reaction mixture was evaporated underreduced pressure and poured into ice water (20 mL) and extracted withEtOAc (2×150 mL). The organic layer was dried over anhydrous Na₂SO₄, andfiltered. to afford a crude compound that was used for the next stepwithout any further purification.

LC-MS (method 21): R_(t)=0.97 min; m/z=214.90 (M+H⁺)

Step b. 3-(2-Bromopyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

To a stirred solution the compound obtained in the previous section,step a (3.4 mg, 15.7 mmol) in THF (20 mL), trifluroacetic anhydride(4.94 g, 23.5 mmol) was added. The resulting solution was heated at 50°C. for 2 h. The reaction mixture was evaporated under vacuum, pouredinto ice water (30 mL) and extracted with EtOAc (2×50 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and the filtratedsolution was concentrated to get a crude residue that was purified byflash column chromatography on silica using 25% EtOAc in petroleum etherto afford the title compound (3.2 g, 69%) as of white solid. LC-MS(method 15): R_(t)=4.15 min; m/z=293.51 (M+H⁺).

Reference Example 323-Bromo-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridine

To a stirred solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg,2.52 mmol) in DMF, NaH (60%) (201 mg, 5.04 mmol) was added at 0° C. andit was stirred for 15 min. Then, 1-bromo-2-methoxyethane (420 mg, 3.02mmol) was added and the reaction mixture was stirred at rt for 2 h. Thereaction mixture was quenched with water and extracted with EtOAc. Theorganic layer was dried over anhydrous Na₂SO₄, and it was concentratedunder reduced pressure. The crude compound was purified by flash columnchromatography on 230-400 silica using 45% EtOAc in pet ether as aneluent to afford the title compound (430 mg, 66%) as a gummy solid.

LC-MS (method 24): R_(t)=2.63 min; m/z=258.01 (M+2H+).

Following a similar procedure to that described in reference example 32,but using in each case the corresponding starting materials, thefollowing compounds were obtained:

Refer- ence exam- Starting HPLC R_(t) ple Compound name material method(min) m/z 32a 3-Bromo-1-ethyl- 3-Bromo-1H- 25 1.70 226.041H-pyrazolo[4,3- pyrazolo]4,3- (M+H⁺) b]pyridine pyrazolo[4,3-b]pyridine and ethyl iodide 32b 3-Bromo-1- 3-Bromo-1H- 6 1.54 212.05methyl- pyrazolo[4,3- (M+H⁺) 1H-pyrazolo b[pyridine [4,3-b]pyridine andmethyl iodide

Reference Example 333-Bromo-1-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridine

To a stirred solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (800 mg,4.03 mmol), in acetonitrile (10 mL) Cs₂CO₃ (3940 mg, 12.09 mmol),2-(2-chloroethyl)-1-methyl-1H-imidazole (640 mg, 4.43 mmol) and NaI (303mg, 2.02 mmol), were added at RT. The reaction mixture was heated at 90°C. overnight. The crude reaction was filtered through a celite pad,washed with EtOAc (50 mL), and the solution was evaporated to dryness.The crude compound was purified twice by column chromatography reversephase with 10 mM Ammonium acetate/Acetonitrile to afford to afford thetitle compound (430 mg, 35%) as a gummy solid.

LC-MS (method 26): R_(t)=1.99 min; m/z=306.0 (M+H⁺).

Reference Example 341-Methyl-3-(trimethylstannyl)-1H-pyrazolo[4,3-b]pyridine

Following a similar procedure to that described in reference example 30,but using reference example 32b, instead of reference example 6b, thedesired compound was obtained.

Example 13-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

Step a. 2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile

To a stirred solution of reference example 2 (800 mg, 3.16 mmol) in 1,4-dioxane (5 mL), reference example 1 (928 mg, 3.47 mmol), CsF (948 mg,6.32 mmol) and CuI (119 mg, 0.63 mmol) were added. The resultingsolution was degassed with nitrogen for 5 minutes, and then Pd (PPh₃)₄(358 mg, 0.31 equiv) was added. The reaction mixture was again degassedfor another 5 min, and then heated at 110° C., for 16 h. The crudereaction was filtered through celite pad, washed with EtOAc (50 mL), andthe filtrated solution was evaporated to dryness. The crude compound waspurified by flash column chromatography in 230-400 silica gel 20% ofEtOAc/pet-ether to afford the title compound (500 mg, 57%) as a lightyellow solid.

LC-MS (method 6): R_(t)=1.66 min; m/z=277.54 (M+H⁺).

Step b.2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-N-hydroxyisonicotinimidamide

To a stirred solution the compound obtained in the previous section,step a (300 mg, 1.08 mmol) in EtOH/MeOH (1:1) (10 mL), 50% NH₂OH.HClaqueous solution (300 mg, 2.16 mmol) was added. The resulting solutionwas heated to 60° C. for 5 h. The reaction mixture was evaporated undervacuum, poured into ice water (20 mL) and extracted with EtOAc (2×80mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and thefiltrated solution was concentrated to get the title compound (320 mg,95%), as a gummy solid. LC-MS (method 6): R_(t)=1.47 min; m/z=310.27(M+H⁺).

Step c.3-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

To a stirred solution the compound obtained in the previous section,step b (300 mg, 0.97 mmol) in THF (10 mL), trifluroacetic anhydride (243mg, 1.16 mmol) was added. The resulting solution was heated at 50° C.for 4 h. The reaction mixture was evaporated under vacuum, poured intoice water (20 mL) and extracted with EtOAc (2×80 mL). The organic layerwas dried over anhydrous Na₂SO₄, filtered and the filtrated solution wasconcentrated to get a crude residue that was purified by prep HPLC toafford the title compound (70 mg, 18.6%) as an off white solid.

LC-MS (method 6): R_(t)=2.00 min; m/z=388.28 (M+H⁺).

Preparative HPLC Conditions: Column/dimensions: PRONTOSIL C18 (20×250mm), 10.0 μm, Mobile phase: 0.1% FA in water:Acetonitrile (A:B);Gradient (Time/% B): 0/20, 1/20, 10/80, 10.1/98, 14/98, 14.1/20, 17/20,Flow rate: 20 ml/min

Following a similar procedure to that described in example 1, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

Starting HPLC R_(t) Example Compound name material method (min) m/z 1a3-(2-(1-Propyl-1H-pyrrolo[2,3-c]pyridin- Reference 15 4.25 374.295-yl)pyridin-4-yl)-5-(trifluoromethyl) example 2a (M + H⁺)1,2,4-oxadiazole

1b 1-Butyl-N,N-dimethyl-5-(4-(5- Reference 15 3.96 459.38(trifluoromethyl)-1,2,4-oxadiazol-3- example 3 (M + H⁺)yl)pyridin-2-yl)-1H-pyrrolo[2,3- c]pyridine-2-carboxamide

1c N,N-Diethyl-3-((4′-(5-(trifluoromethyl)- Reference 6 1.84 422.411,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5- example 4 (M + H⁺)yl)oxy)propan-1-amine (obtained as hemiformate salt)

1d 1-Butyl-N-ethyl-5-(4-(5-(trifluoromethyl)- Reference 16 6.74 459.411,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H- example 3b (M + H⁺)pyrrolo[2,3-c]pyridine-2-carboxamide

1e 4-(3-((4′-(5-(Trifluoromethyl)- Reference 15 3.35 436.191,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5- example 6a (M + H⁺)yl)oxy)propyl)morpholine (obtained as hemitrifluoroacetate salt)

1f 3-(5′-(3-(4,4-Difluoropiperidin-1- Reference 16 6.82 470.26yl)propoxy)-[2,2′-bipyridin]-4-yl)-5- example 6 (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole (obtained as diformate salt)

1g 3-(2-(3-(Piperidin-1-ylmethyl)-1-propyl- Reference 14 2.48 471.11H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4- example 5a (M + H⁺)yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (obtained as trifluoroacetatesalt)

1h 4-((1-Propyl-5-(4-(5-(trifluoromethyl)- Reference 14 2.79 473.21,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H- example 5b (M + H⁺)pyrrolo[2,3-c]pyridin-3- yl)methyl)morpholine

1i N-Butyl-3-methoxy-N-(4′-(5- Reference 16 6.63 450.37(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 7 (M + H⁺)[2,2′-bipyridin]-5-yl)propanamide

1j N-(Cyclopropylmethyl)-N-methyl-4′-(5- Reference 16 7.05 376.33(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 8 (M + H⁺)[2,2′-bipyridin]-5-amine

1k N¹,N¹-Diethyl-N³-(4′-(5-(trifluoromethyl)- Reference 6 1.69 421.391,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5- example 9 (M + H⁺)yl)propane-1,3-diamine (**)

1l N-(3-(4,4-Difluoropiperidin-1-yl)propyl)- Reference 16 6.88 483.42N-methyl-4′-(5-(trifluoromethyl)-1,2,4- example 10 (M + H⁺)oxadiazol-3-yl)-[2,2′-bipyridin]-5-amine

1m N,N-Diethyl-3-(2-(4-(5-(trifluoromethyl)- Reference 15 2.53 423.221,2,4-oxadiazol-3-yl)pyridin-2- example 11 (M + H⁺)yl)pyrimidin-5-yloxy)propan-1-amine (obtained as hemiformate salt)

1n N¹,N¹-Diethyl-N³-methyl-N³-(4′-(5- Reference 6 2.08 435.40(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 12 (M + H⁺)2,2′-bipyridin-5-yl)propane-1,3-diamine (obtained as formate salt)

1o 3-(2-(1-(Tetrahydro-2H-pyran-4-yl)-1H- Reference 6 1.76 416.33pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 14 (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1p N-Ethyl-N-phenethyl-3-((4′-(5- Reference 6 2.12 498.48(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 15 (M + H⁺)[2,2′-bipyridin]-5-yl)oxy)propan-1-amine

1q 2-Phenyl-N-(4′-(5-(trifluoromethyl)- Reference 16 6.38 426.351,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5- example 16 (M + H⁺)yl)acetamide

1r 3-(2-(1-((Tetrahydro-2H-pyran-4- Reference 16 6.33 430.38yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6- example 14a (M + H⁺)yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole

1s 3-(4′-(2-(4,4-Difluoropiperidin-1- Reference 16 5.56 456.16yl)ethoxy)-[2,2′-bipyridin]-4-yl)-5- example 17 (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1t 4-(2-((4′-(5-(Trifluoromethyl)-1,2,4- Reference 16 5.71 422.14oxadiazol-3-yl)-[2,2′-bipyridin]-4- example 17a (M + H⁺)yl)oxy)ethyl)morpholine

1u N,N,1-Trimethyl-5-(4-(5- Reference 16 5.84 417.37(trifluoromethyl)-1,2,4-oxadiazol-3- example 3a (M + H⁺)yl)pyridin-2-yl)-1H-pyrrolo[2,3- c]pyridine-2-carboxamide (obtained asditrifluoroacetate salt)

1v 3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H- Reference 15 3.69 440.32pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5- example 19 (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1w 1-Butyl-N,N-diethyl-5-(4-(5- Reference 18 6.15 487.2(trifluoromethyl)-1,2,4-oxadiazol-3- example 3c (M + H⁺)yl)pyridin-2-yl)-1H-pyrrolo[2,3- c]pyridine-2-carboxamide

1x 3-(2-(1-(2-Methoxyethyl)-1H- Reference 16 6.30 390.32pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5- example 2b (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1y 2-(4,4-Difluoropiperidin-1-yl)-N-(4′-(5- Reference 18 5.39 469.1(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 20 (M + H⁺)[2,2′-bipyridin]-4-yl)acetamide

1z N-(2-(4,4-Difluoropiperidin-1-yl)ethyl)- Reference 16 5.90 455.394′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3- example 21 (M + H⁺)yl)-[2,2′-bipyridin]-4-amine (obtained as pentatrifluoroacetate salt)

1aa 3-(2-(3-(Piperidin-1-ylmethyl)-1H- Reference 18 4.32 430.1pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)- example 22 (M + H⁺)5-(trifluoromethyl)-1,2,4-oxadiazole (obtained as sesquitrifluoroacetatesalt)

1ab 3-(2-(1-(2-(4,4-Difluoropiperidin-1- Reference 16 6.77 479.42yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-6- example 23 (M + H⁺)yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole

1ac 1-Methyl-N-(4′-(5-(trifluoromethyl)- Reference 6 1.75 433.401,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5- example 16a (M + H⁺)yl)piperidine-4-carboxamide (obtained as hemiformate salt)

1ad 3-Phenyl-N-(4′-(5-(trifluoromethyl)- Reference 18 5.60 440.11,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4- example 24 (M + H⁺)yl)propanamide

1ae 2-Cyclobutyl-N-(4′-(5-(trifluoromethyl)- Reference 18 5.49 404.011,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4- example 16b (M + H⁺)yl)acetamide (obtained as hemitrifluoroacetate salt)

1af N-(Piperidin-3-yl)-4′-(5-(trifluoromethyl)- Reference 18 3.90 419.11,2,4-oxadiazol-3-yl)-[2,2′-bipyridine]-4- example 16c (M + H⁺)carboxamide (*)

1ag 3-(5′-(3-(1H-Pyrazol-1-yl)propoxy)-[2,2′- Reference 16 6.34 417.20bipyridin]-4-yl)-5-(trifluoromethyl)-1,2,4- example 27 (M + H⁺)oxadiazole

1ah (l-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4- Reference 6 1.73 404.36oxadiazol-3-yl)pyridin-2-yl)-1H- example 5c (M + H⁺)pyrrolo[2,3-c]pyridin-3-yl)methanol (obtained as sesquitrifluoroacetatesalt)

1ai 3-(2-(3-(Methoxymethyl)-1-propyl-1H- Reference 15 4.10 418.34pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5- example 5c (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1aj (1-butyl-5-(4-(5-(trifluoromethyl)-1,2,4- Referece 6 1.80 418.27oxadiazol-3-yl)pyridin-2-yl)-1H- example 5 (M + H⁺)pyrrolo[2,3-c]pyridin-3-yl)methanol

1ak 3-(2-(1H-Pyrrolo[3,2-c]pyridin-6- Referece 16 5.80 332.24yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- example 25 (M + H⁺)oxadiazole (obtained as hemiformate salt)

1al 3-(2-(1-(Pyridin-4-ylmethyl)-1H- Referece 6 1.57 423.33pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 25 (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole (obtained as tritrifluoroacetatesalt)

1am N-((1-Methylpiperidin-4-yl)methyl)-4′-(5- Referece 16 5.10 447.39(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 16d (M + H⁺)[2,2′-bipyridine]-4-carboxamide (obtained as hemipentatrifluoroacetatesalt)

1an N-((1-Methylpiperidin-4-yl)methyl)-4′-(5- Referece 18 4.32 447.1(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 16e (M + H⁺)[2,2′-bipyridine]-5-carboxamide (obtained as hemipentacetate salt)

1ao 3-(2-(1-(1-(2,2,2- Referece 6 1.97 497.34Trifluoroethyl)piperidin-4-yl)-1H- example 28 (M + H⁺)pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

1ap 3-(2-(1-Methyl-3-(1H-pyrazol-4-yl)-1H- Referece 18 3.96 412.1pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5- example 19a (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1aq 3-(2-(1-Butyl-3-(1-methyl-1,2,3,6- Referece 16 6.42 483.41tetrahydropyridin-4-yl)-1H-pyrrolo[2,3- example 29 (M + H⁺)c]pyridin-5-yl)pyridin-4-yl)-5- (trifluoromethyl)-1,2,4-oxadiazole

1ar 1-(2-Methoxyethyl)-N,N-dimethyl-5-(4- Referece 20 4.17 461.28(5-(trifluoromethyl)-1,2,4-oxadiazol-3- example 3d (M + H⁺)yl)pyridin-2-yl)-1H-pyrrolo[2,3- c]pyridine-2-carboxamide

1as 3-(2-(1-(2-Methoxyethyl)-3-(1H-pyrazol- Referece 18 4.27 456.14-yl)-1H-pyrrolo[2,3-c]pyridin-5- example 19b (M + H⁺)yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole (obtained ashemiformate salt)

1at 3-(2-(1-Methyl-1H-pyrrolo[2,3-c]pyridin- 5-Bromo-1- 20 3.87 346.15-yl)pyridin-4-yl)-5-(trifluoromethyl)- methyl-1H- (M + H⁺)1,2,4-oxadiazole (obtained as pyrrolo[2,3- hemiformatehemitrifluoroacetate salt) c]pyridine

1au 3-(2-(1-(2-Methoxyethyl)-1H- Referece 20 3.96 390.26pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 25a (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1av 3-(2-(1-(Pyridin-3-ylmethyl)-1H- Referece 18 3.78 423.1pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 25b (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1aw 3-(2-(1-(Pyridin-2-ylmethyl)-1H- Referece 18 3.75 423.1pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 25c (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

1ax 2-(Methyl(3-((4′-(5-(trifluoromethyl)- Referece 22 4.38 424.381,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5- example 6cyl)oxy)propyl)amino)ethan-1-ol (obtained as formate salt)

1ay 3-(2-(1-(2-Methoxyethyl)-1H- Referece 23 5.39 390.9pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)- example 25d (M + H⁺)5-(trifluoromethyl)-1,2,4-oxadiazole

1az 3-(2-(2-(2-Methoxyethyl)-2H- Referece 20 4.50 391.18pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)- example 25e (M + H⁺)5-(trifluoromethyl)-1,2,4-oxadiazole

1aaa 3-(2-(1-(2-Methoxyethyl)-1H- Referece 27 4.65 391.27pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)- example 32 (M + H⁺)5-(trifluoromethyl)-1,2,4-oxadiazole

1aab 3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin- Referece 27 4.83 361.243-yl)pyridin-4-yl)-5-(trifluoromethyl)- example 32a (M + H⁺)1,2,4-oxadiazole

1aac 3-(2-(1-(2-(1-Methyl-1H-imidazol-2- Referece 27 4.27 441.25yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3- example 33 (M + H⁺)yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole

1aad 3-(2-(1-((1-Methyl-1H-pyrazol-4- Referece 6 1.74 426.31yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6- example 25f (M + H⁺)yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole

(*) TFA was added for complete Boc deprotection (**) obtained with 0.7equiv of TFA and 0.3 equiv of formic acid

Example 2N-Methyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine(as Formate Salt)

Step a. 5′-(3-(Methylamino)propoxy)-[2,2′-bipyridine]-4-carbonitrile

To a stirred solution of reference example 13 (250 mg, 1.01 mmol) in 1,4-dioxane (20 mL), reference example 1 (16) (299 mg, 1.12 mmol), CsF(308 mg, 2.03 mmol) and CuI (38 mg, 0.20 mmol) wee added. The resultingsolution was degassed with nitrogen for 15 minutes, then Pd(PPh₃)₄ (117mg, 0.1 mmol) was added and heated at 110° C. for 16 h. The reaction wasfiltered through celite pad, washed with EtOAc (50 mL). The filtratedsolution was evaporated to dryness. The crude residue was purified bycolumn chromatography on 230-400 silica with 90% EtOAc/pet ether aseluent to afford the title compound (180 mg, 65%) as a gummy solid.LC-MS (method 14): R_(t)=1.45 min; m/z=269.1 (M+H⁺).

Step b. Tert-butyl(3-((4′-cyano-[2,2′-bipyridin]-5-yl)oxy)propyl)(methyl) carbamate

To a stirred solution of the compound obtained in the previous section,step a (180 mg, 0.67 mmol) in acetonitrile (10 mL), Boc anhydride (219mg, 1.0 mmol), and TEA (0.27 mL, 2.01 mmol), were added. The resultingmixture was stirred rt for 16 h. The reaction mixture was evaporatedunder vacuum to afford a crude compound that was used for the next stepwithout any further purification (200 mg, 80%)

LC-MS (method 15): R_(t)=3.75 min; m/z=369.08 (M+H⁺).

Step c. Tert-butyl(3-((4′-(N-hydroxycarbamimidoyl)-[2,2′-bipyridin]-5-yl)oxy)propyl)(methyl)carbamate

To a stirred solution of the compound obtained in the previous section,step b (200 mg, 0.54 mmol) in EtOH/MeOH (4:1), 50% NH₂OH.HCl aqueoussolution (75 mg, 1.08 mmol) and NaHCO₃ (91 mg, 1.08 mmol) were added.The resulting mixture was stirred at 50° C. for 3 h. The reactionmixture was concentrated to get a crude residue that was diluted withEtOH and filtered thorough a Buckner funnel. The filtered solution wasconcentrated to dryness to afford the title compound (170 mg (78%) as alight brown gummy solid that was used in the next step withoutpurification.

LC-MS (method 15): R_(t)=2.89 min; m/z=402.21 (M+H⁺).

Step d.N-Methyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine Formate

To a stirred solution of the compound obtained in the previous section,step c (150 mg, 0.37 mmol) in THF trifluroacetic anhydride (0.1 mL, 0.56mmol) was added. The resulting mixture was heated at 70° C. and TFA (0.5mL, 0.64 mmol) was added. It was stirred at 50° C. for 2 h. The solventswere evaporated under vacuum and the crude residue was poured in to icewater and extracted with EtOAc. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The crude compound waspurified by prep HPLC to afford the title compound (65 mg, 45%) as apink solid.

LC-MS (method 15): R_(t)=2.79 min; m/z=380.15 (M+H⁺).

Prep.HPLC conditions: Column/dimensions: SYNERGY POLAR C18(21.2×250 mm),5 μm Mobile phase: 0.1% FA: Acetonitrile (A:B) Gradient (Time/% B):0/20, 1/20, 7/50, 10/50, 10.1/98, 13/98, 13.120, 16/20. Flow rate: 20ml/min.

Example 31-(1-Butyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine

To a stirred solution of example 1 (400 mg, 1 mmol) in n-butanol, HCHO(300 mg, 10 mmol) and dimethyl amine HCl salt (815 mg 10 mmol) wereadded. The resulting mixture was stirred at 120° C. for 16 h. Thereaction mixture concentrated to get a crude compound that was purifiedby prep-HPLC to afford the title compound (38 mg, 8.6%) as a pink stickysolid.

LC-MS (method 15): R₁=3.37 min; m/z=445.39 (M+H⁺).

Preparative HPLC Conditions: Column/dimensions: XSELECT C18 (19*250*5μm) Mobile phase A: 0.1% FA in water (aq) Mobile phase B: Acetonitrile(org) Gradient (Time/% B) 0/10, 1/10, 5/30, 9/30, 9.1/100, 11/100,11.1/10, 13/10. Flow rate: 18 ml/min Solubility: Methanol+ THF.

Example 43-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

Step a.2-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)isonicotinonitrile

To a stirred solution of reference example 26 (900 mg, 3.19 mmol) intoluene (25 mL), reference example 1 (1100 mg, 4.15 mmol) was added anddegassed for 10 min with nitrogen gas. Then, PdCl₂(PPh₃)₂ (112 mg, 0.16mmol) was added and the resulting solution was degassed for another 5min and heated at 100° C. for 16 h. The reaction mixture wasconcentrated under reduced pressure to afford a crude residue that waspurified by column chromatography to afford the title compound (800 mg,82.2%).

LC-MS (method 1): R_(t)=2.44 min; m/z=306.24 (M+H⁺).

Step b. 2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)isonicotinonitrile

To a stirred solution of the compound obtained in the previous section,step a (800 mg, 2.62 mmol) in DCM (15 mL), TFA (10 mL) was added and itwas stirred at rt for 48 h. The reaction mixture was concentrated underreduced pressure to afford a crude residue that was purified by columnchromatography to afford the title compound (400 mg, 69.0%).

LC-MS (method 1): R_(t)=1.85 min; m/z=222.13 (M+H⁺).

Step c. N-hydroxy-2-(1H-pyrazolo[4,3-b]pyridin-3-yl)isonicotinimidamide

Following a similar procedure to that described in example 1, section b,but using the compound obtained in the previous section, step b, insteadof 2-(1-butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile, thedesired compound was obtained.

LC-MS (method 14): R_(t)=1.25 min; m/z=255.1 (M+H⁺).

Step d.3-(2-(1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

Following a similar procedure to that described in example 1, section c,but using the compound obtained in the previous section, step c, insteadof2-(1-butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-N-hydroxyisonicotinimidamide,the desired compound was obtained.

LC-MS (method 6): R_(t)=1.98 min; m/z=333.20 (M+H⁺).

Example 5N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)piperidine-3-carboxamide(as Hemiformate Salt)

Step a. tert-butyl3-((4′-cyano-[2,2′-bipyridin]-4-yl)carbamoyl)piperidine-1-carboxylate

To a stirred solution of reference example 16c (3 g, 7.81 mmol) intoluene (30 mL), 2-bromoisonicotinonitrile (2.14 g, 11.71 mmol), andhexamethylditin (2.8 mL, 13.67 mmol) were added. The resulting solutionwas degassed with argon for 10 minutes, then Pd(PPh₃)₄ (902 mg, 0.781mmol) was added. The resulting mixture was degassed for 5 minutes andheated at 110° C. for 16 h. The reaction mixture was diluted with waterand extracted with EtOAc (2×20 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to get a cruderesidue that was purified by column chromatography using 10% EtOAc inpetroleum ether to afford the title compound (800 mg, 25.1%)

LC-MS (method 1): R_(t)=2.62 min; m/z=408.31 (M+H⁺).

Step b. N-(4′-cyano-[2,2′-bipyridin]-4-yl)piperidine-3-carboxamidehydrochloride

To a stirred solution of the compound obtained in the previous section,step a, (200 mg, 0.486 mmol) in DCM (2 mL), 2M HCl solution indiethylether (3 mL) was added at 0° C. The reaction mixture was allowedto stir at rt for 2 h. The resulting mixture was concentrated and thecrude residue was triturated with n-pentane and diethyl ether. It wasfiltered under reduced pressure to afford 800 mg (54%) of the titlecompound

LC-MS (method 1): R_(t)=1.54 min; m/z=308.29 (M+H⁺).

Step c.N-(4′-(N-hydroxycarbamimidoyl)-[2,2′-bipyridin]-4-yl)piperidine-3-carboxamidehydrochloride

To a stirred solution of the compound obtained in the previous section,step b, (50 mg, 0.16 mmol) in EtOH (6 mL), hydroxylamine hydrochloride(22 mg, 0.32 mmol), and NaHCO₃ (27 mg, 0.32 mmol) in water (2 mL) wereadded. The reaction mixture was stirred at 70° C. for 6 h. The resultingsolution was concentrated to dryness and the crude residue was dilutedwith EtOH and filtered thorough a Buckner funnel to remove the NaHCO₃.The filtered solution was concentrated to afford the title compound (45mg, 82%) that was used in next step without further purification.

LC-MS (method 14): R_(t)=1.26 min; m/z=341.1 (M+H⁺).

Step d.1-(2,2,2-trifluoroacetyl)-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)piperidine-3-carboxamide

To a stirred solution of the compound obtained in the previous section,step c, (40 mg, 0.11 mmol) in THF (5 mL), trifluroacetic anhydride (0.1mL) was added. The resulting mixture was stirred at 70° C. for 3 h. Thereaction mixture was concentrated under reduced pressure to get a cruderesidue that was purified by Prep HPLC to afford the title compound (16mg, 28%) as an off white solid.

LC-MS (method 14): R_(t)=2.82 min; m/z=515.1 (M+H⁺).

Preparative HPLC Conditions: Column/dimensions Prontosil C18 (20×250mm), 10 μm Mobile phase: 0.1% Ammonium Acetate in water:Acetonitrile(A:B) Gradient (Time/% B): 0/20, 1/20, 5/70, 15/700, 15.1/100 Flow rate:20 ml/miN Solubility: ACN+THF+WATER

Step e.N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)piperidine-3-carboxamideHemiformate

To a stirred solution of the compound obtained in the previous section,step c, (16 mg, 0.03 mmol) in MeOH (5 ML), K₂CO₃ (4.7 mg, 0.034 mmol)were added. The resulting mixture was stirred at rt for 16 h. Thereaction mixture was concentrated under reduced to get a crude residuethat was purified by Prep HPLC to afford the title compound (6 mg, 46%)as an off white solid.

LC-MS (method 6): R_(t)=1.84 min; m/z=419.34 (M+H⁺).

Preparative HPLC Conditions: Column/dimensions: SUN FIRE C18 (19*150 mm,5 um) Mobile phase A: 0.1% FA in water (aq) Mobile phase B: Acetonitrile(org) Gradient (Time/% B): 0/10, 1/10, 5/25, 8/25, 8.1/98, 10/98,10.1/10, 12/10. Flow rate: 18 ml/min Solubility: Acetonitrile+ THF

Example 63-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

Step a. 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)isonicotinonitrile

To a stirred solution of 2-bromoisonicotinonitrile (500 mg, 2.7 mmol) intoluene (25 mL), 1H-pyrazolo[3,4-b]pyridine (0.6432 g, 5.4 mmol), andK₂CO₃ (1.86 g, 13.5 mmol) were added followed by CuI (0.256 g, 1.35mmol). The resulting solution was degassed with nitrogen for 15 minutes,and trans N,N-dimethylcyclohexane-1,2-diamine (0.192 g, 1.35 mmol) wasadded. The resulting reaction was heated at 110° C. for 16 h. Thereaction mixture was evaporated under vacuum to get a crude residue thatwas purified by prep HPLC to afford the title compound (300 mg, 29.3%)

LC-MS (method 6): R_(t)=1.626 min; m/z=222.01 (M+H⁺).

Step b. N-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)isonicotinimidamide

To a stirred solution the compound obtained in the previous section,step a (300 mg, 1.0 mmol) in EtOH (5 mL), 50% NH₂OH.HCl aqueous solution(179 mg, 2.1 mmol) and Na₂CO₃ (296 mg, 2.8 mmol) in H₂O (5 mL) wereadded. The resulting solution was stirred at rt for 18 h. The reactionmixture was evaporated under vacuum, to get a crude compound that wasused for the next step without any further purification.

LC-MS (method 6): R_(t)=1.16 min; m/z=255.12 (M+H⁺).

Step c.3-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

To a stirred solution the compound obtained in the previous section,step b (300 mg, 1.2 mmol) in THF (10 mL), trifluroacetic anhydride (252mg, 1.2 mmol) was added. The resulting solution was heated at 70° C. for3 h. The reaction mixture was evaporated under vacuum to get a cruderesidue that was purified by prep HPLC to afford the title compound (115mg, 29.3%) as an off white solid.

LC-MS (method 20): R_(t)=4.79 min; m/z=333.11 (M+H⁺).

Example 7N,N-Dimethyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,7-bipyridin]-5-yl)oxy)propan-1-amine

To a stirred solution of reference example 31 (300 mg, 1.0 mmol) intoluene (3 mL), reference example 30 (928 mg, 3.47 mmolv) was added. Theresulting solution was degassed with nitrogen for 15 minutes, and thenPd (PPh₃)₄ (115 mg, 0.1 mmol) was added. The reaction mixture was againdegassed for another 5 min, and then heated at 110° C., for 16 h. Thecrude reaction was filtered through a celite pad, washed with EtOAc (50mL), and the filtrated solution was evaporated to dryness. The crudecompound was purified by prep HPLC to afford the title compound (65 mg,16%) as a light pink solid.

LC-MS (method 16): R_(t)=4.49 min; m/z=394.29 (M+H⁺).

Following a similar procedure to that described in example 7, but usingthe corresponding starting material, the following compound wasobtained:

Starting HPLC R_(t) Example Compound name material method (min) m/z 7a3-(2-(1-Methyl-1H-pyrazolo[4,3- Reference 27 4.60 347.30b]pyridin-3-yl)pyridin-4-yl)-5- example 34 (M + H⁺)(trifluoromethyl)-1,2,4-oxadiazole

Example 8 HDAC6 and HDAC2 Enzyme Inhibition Assay

Method:

A fluorimetric assay was used for testing the activity of compounds ofthe invention against HDAC6 and HDAC2. Recombinant proteins referenceand amounts used in each assay are listed in the Table below.

ng/ Assay Reference reaction HDAC2 BPS Bioscience 7.5 Inc. #50002 (fulllength with C- terminal His tag) HDAC6 BPS Bioscience 20 Inc. #50006(full length with N- terminal GST tag)

The compounds were dissolved in DMSO. Serial dilutions were prepared inDMSO and then diluted 1:10 in HDAC assay buffer (Tris-buffered solution,BPS Bioscience Inc. #50031). 5 μl of the compound dilution was added toa 50 μl reaction so that the final concentration of DMSO was 1%.

The compounds were pre-incubated in duplicate at RT for 3 hours in amixture containing HDAC assay buffer, 5 μg BSA and recombinant HDACenzyme (see table above). The enzymatic reactions were initiated by theaddition of a fluorogenic, acetylated peptide substrate based on ahistone protein (BPS Bioscience Inc. #50037) to a final concentration of10 μM. The enzymatic reaction proceeded for 30 minutes at 37° C. Then,50 μl of 2×HDAC Developer, which contains peptidase activity andTrichostatin A (BPS Bioscience Inc. #50030) was added and the plate wasincubated at RT for an additional 15 minutes. Fluorescence intensity wasmeasured at an excitation of 360 nm and an emission of 460 nm using aTecan Infinite M1000 microplate reader.

Trichostatin A (TSA, Selleckchem # S1045) was used as referenceinhibitor.

The fluorescent intensity data were analyzed using the computer softwareGraphpad Prism (GraphPad Software, San Diego, Calif.). 100% activity wasdefined as the fluorescent intensity (Ft) in the absence of thecompound. 0% activity was defined as the fluorescent intensity (Fb) inthe absence of the enzyme. The percent activity in the presence of eachcompound was calculated according to the following equation: %activity=(F—Fb)/(Ft—Fb), where F=the fluorescent intensity in thepresence of the compound.

Results:

The results obtained in the above assays with compounds of the inventionare shown in the table below:

Exam- HDAC6 HDAC2 ple % inh @ % inh @ # 1 μM 1 μM 1 79 NT 1a NT NT 1b 84NT 1c 89 3 1d 78 NT 1e 84 9 1f 71 16 1g 96 38 1h 96 NT 1i NT NT 1j 69 101k 95 27 1m 81 NT 1n NT NT 1o 97 23 1p NT NT 1q 73 11 1r 92 NT 1s NT NT1t 88 NT 1u 98 19 1v 66 3 1w 86 6 1x 95 16 1y 92 27 1z 97 46 1aa 92 NT1ab 93 38 1ac 78 18 1ad NT NT 1ae 85 5 1af NT NT 1ag NT NT 1ah 96 35 1aiNT NT 1aj NT NT 1ak 90 14 1al 92 31 1am NT NT 1an NT NT 1ao NT NT 1ap 866 1aq 89 2 1ar NT NT 1as NT NT 1at NT NT 1au 85 19 1av NT NT 1aw 81 151ax NT NT 1ay NT NT 1az NT NT 2 NT NT 3 90 30 4 96 25 5 95 29 6 NT NT 7NT NT NT: Not tested

Example 9 In Vitro Cell-Based Assay

Method:

In order to determine the cellular activity of HDAC6 upon treatment withHDAC6 inhibitors, acetylation levels of Alpha-Tubulin (a HDAC6-specificsubstrate) were measured by Western Blot. For this, MOLP8 cells wereseeded in 6-well plates at a cell density of 500.000 cells/well andtreated with the selected compounds at 5 and 1 μM for 18 h at 37° C. and5% CO₂ in a humidified tissue culture incubator. Consecutively, cellpellets were collected and whole protein extracts prepared using RIPAbuffer (SIGMA) supplemented with 1× protease inhibitors (cOmplete mini,Roche). Protein concentration was determined with Bradford's reagent(Bio-Rad) as per manufacturer's instructions, and 7 μg of total proteinwere loaded into pre-cast 10% NuPAGE Novex gels (Life Technologies).Gels were run in MOPS-SDS buffer (Life Technologies) and proteins weretransferred using the iBlot 2 Dry Blotting System (Life Technologies).Blots were subsequently rinsed in distilled water and stained withPonceau S solution (SIGMA). Blots were then washed in distilled water toremove Ponceau excess and scanned with the Epson Perfection V600 Photoprofessional Scanner. After this, blots were de-stained and blocked in5% milk/PBS-Tween 0.1% for 1 h at room temperature followed byincubation with anti-Acetyl-alpha Tubulin (SIGMA cat. # T7451, 1:10.000dilution) and anti-Beta-actin (SIGMA, cat. # A5316, 1:2.000 dilution)primary antibodies in 5% milk/PBS-T 0.1%, overnight at 4° C. on ashaking platform. After incubation, blots were washed 3 times for 5minutes each in PBS-Tween 0.5% and incubated with anti-mouseHRP-conjugated secondary antibody (Jackson Immuno Research, cat.#115-035-068) at 1:8.000 in 5% milk/PBS-Tween 0.1%, 1 h at roomtemperature on a shaking platform. After 3 washes of 5 minutes each withPBS-Tween 0.5% and 1 wash in PBS 1×, blots were developed with ECL Plus(GE Healthcare) and the chemiluminescent reaction imaged with the G:BoxChemi XRQ (Syngene) imaging system. WB and Ponceau images were analysedwith ImageJ software, WB band intensities normalized by either totalprotein or Beta-actin content and made relative to ACY-1215 1 μM(equivalent to 100%). ACY-1215 is a HDAC6 inhibitor, and is also knownas ricolinostat, with chemical name2-(diphenylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-5-pyrimidinecarboxamide.Percentage of band intensities was classified as follows:

Relative band intensity (%) Classification <50 −  50-150 + 150-300++ >300 +++

Results:

The results obtained in this assay with compounds of the invention areshown in the table below:

Cellular Cellular activity activity Example @ 1 μM @ 5 μM 1 − + 1a − ++1b + ++ 1c + ++ 1d + ++ 1e + ++ 1f − ++ 1g + +++ 1h + ++ 1i − + 1j − ++1k + + 1l − + 1m − + 1n − + 1o ++ +++ 1p − ++ 1q + ++ 1r ++ ++ 1s − + 1t− + 1u +++ +++ 1v + +++ 1w + ++ 1x ++ +++ 1y + ++ 1z + ++ 1aa + + 1ab ++++ 1ac + ++ 1ad + + 1ae + + 1af + + 1ag − + 1ah + ++ 1ai − + 1aj + +1ak + ++ 1al ++ ++ 1am + + 1an + + 1ao + ++ 1ap + ++ 1aq ++ ++ 1ar + +1as + + 1at − + 1au + ++ 1av + ++ 1aw + ++ 1ax + + 1ay − + 1az − +1aaa + + 1aab + + 1aac + ++ 1aad + ++ 2 − + 3 + +++ 4 ++ +++ 5 ++ ++6 + + 7 − + 7a + ++

The data provided in Examples 8 and 9 show that compounds of Formula (I)exhibit potent HDAC6 inhibitory activity, including in cells.Furthermore, compounds of the invention show selectivity towards HDAC6vs HDAC2, based on the data obtained for representative compounds of theinvention against HDAC2, as shown in example 8.

1. A compound of Formula (I) or a salt thereof:

wherein m is 0, 1 or 2; each R¹ is independently selected from halo, methyl and trifluoromethyl; A is selected from: i) a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl ring that is fully aromatic, and ii) a 9- or 10-membered bicyclic heteroaryl ring consisting of a 5- or 6-membered monocyclic heteroaryl ring fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, wherein the 9- or 10-membered bicyclic heterocyclic ring is linked to the rest of the molecule through the 5- or 6-membered monocyclic heteroaryl ring, wherein A contains one ring N atom at a position adjacent to the ring atom through which ring A is attached to the rest of the molecule, wherein A optionally contains from 1 to 3 additional ring heteroatoms selected independently from N, O and S, and wherein A is optionally substituted with one or two R² and in addition A is optionally substituted with one R³; each R² is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl and —(C₁₋₆ alkylene)-OR⁴; R³ is selected from -L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸, -L⁴-CONR⁹R¹⁰, -L⁵-NR¹¹COR₁₂, —Y-L⁶-OR⁶ and —Y-L⁷- NR⁷R⁸; L¹, L², L³, L⁴ and L⁵ are each independently selected from a bond and C₁₋₆ alkylene; L⁶ and L¹ are each independently selected from C₂₋₆ alkylene; each Y is independently selected from —O—, —NR¹³—, —CONR¹⁴— and —NR¹⁵CO—; each R⁴ is independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl and C₃₋₇ cycloalkyl-C₁₋₆ alkyl; each R⁵ is independently selected from carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein the carbocyclyl, the aryl, the heterocyclyl and the heteroaryl are each optionally substituted with one or more R¹⁶; R⁶ and R¹² are each independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl and -L¹-R⁵; R⁷ and R⁸ are each independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —(C₁₋₆ alkylene)-OR⁴ and -L¹-R⁵; R⁹ and R¹⁰ are each independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —(C₁₋₆ alkylene)-OR⁴ and -L¹-R⁵, or R⁹ and R¹⁰ taken together with the N atom to which they are attached form a saturated 4- to 12-membered heterocyclic ring optionally containing one additional heteroatom selected from N, O and S, wherein said heterocyclic ring is optionally substituted with one or more R¹⁶; R¹¹, R¹³, R¹⁴ and R¹⁵ are each independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl and —(C₁₋₆ alkylene)-OR⁴; each R¹⁶ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —OH, —NR¹⁷R¹⁸, —COR¹⁹, —CN, -L⁸-carbocyclyl, -L⁸-aryl, -L⁸-heterocyclyl and -L⁸-heteroaryl, wherein the carbocyclyl in -L⁸-carbocyclyl, the aryl in -L⁸-aryl, the heterocyclyl in -L⁸-heterocyclyl and the heteroaryl in -L⁸-heteroaryl are each optionally substituted with one or more R²⁰; each L⁸ is independently selected from a bond and C₁₋₆ alkylene; R¹⁷ and R¹⁸ are each independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl and C₃₋₇ cycloalkyl-C₁₋₆ alkyl; R¹⁹ is selected from hydrogen, C₁₋₆ alkyl and C₁₋₆ haloalkyl; and each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —OH, —NR¹⁷R¹⁸, —COR¹⁹ and —CN.
 2. The compound of claim 1, wherein A is selected from: i) a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl ring that is fully aromatic, and ii) a 9- or 10-membered bicyclic heteroaryl ring consisting of a 5- or 6-membered monocyclic heteroaryl ring fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, wherein the 9- or 10-membered bicyclic heterocyclic ring is linked to the rest of the molecule through the 5- or 6-membered monocyclic heteroaryl ring, wherein A contains one ring N atom at a position adjacent to the ring atom through which ring A is attached to the rest of the molecule, wherein A optionally contains from 1 to 3 additional ring N atoms, and wherein A is optionally substituted with one or two R² and in addition A is optionally substituted with one R³.
 3. The compound of claim 1, wherein A is a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl ring that is fully aromatic, wherein A contains one ring N atom at a position adjacent to the ring atom through which ring A is attached to the rest of the molecule, wherein A optionally contains from 1 to 3 additional ring N atoms, and wherein A is optionally substituted with one or two R² and in addition A is optionally substituted with one R³.
 4. The compound of claim 1, wherein A is selected from the cyclic groups listed below:

wherein A is optionally substituted with one or two R² and in addition A is optionally substituted with one R³.
 5. The compound of claim 1, wherein A is selected from the cyclic groups listed below:

wherein A is optionally substituted with one or two R² and in addition A is optionally substituted with one R³.
 6. The compound of claim 1, wherein the compound has formula (IIa) or (IIb), or a salt thereof

wherein one of Z¹, Z² and Z³ is H and the others are independently selected from H and R².
 7. The compound of claim 1, wherein the compound has formula (IIIa) or (IIIb), or a salt thereof

wherein one of Z¹, Z² and Z³ is R³ or H, and the others are independently selected from H and R².
 8. The compound of claim 1, wherein the compound has formula (IVa), or a salt thereof

wherein one of Z¹, Z², Z³ and Z⁴ is selected from R², R³ and H, and the others are independently selected from H and R², with the proviso that only up to two of Z¹, Z², Z³ and Z⁴ are R².
 9. The compound of claim 1, wherein the compound has formula (IVb), or a salt thereof

wherein one of Z¹, Z², Z³ and Z⁴ is selected from R², R³ and H, and the others are independently selected from H and R², with the proviso that only up to two of Z¹, Z², Z³ and Z⁴ are R².
 10. The compound of any one of claims 1 to 9, wherein m is
 0. 11. The compound of any one of claims 1 to 10, wherein R³ is selected from -L¹-R⁵, -L²-OR⁶, -L³-NR⁷R⁸, —CONR⁹R¹⁰, —NR¹¹COR¹² and —Y-L⁷-NR⁷R⁸.
 12. The compound of any one of claims 1 to 11, wherein R³ is -L¹-R⁵.
 13. The compound of any one of claims 1 to 11, wherein R³ is —CONR⁹R¹⁰ or —NR¹¹COR¹².
 14. The compound of any one of claims 1 to 11, wherein R³ is —Y-L⁷-NR⁷R⁸, and Y is selected from —O— and —NR¹³—.
 15. The compound of any one of claims 1 to 11, wherein R³ is —OR⁶, wherein R⁶ is -L¹-R⁵, or R³ is —NR⁷R⁸, wherein one of R⁷ or R⁸ is -L¹-R⁵.
 16. The compound of any one of claims 1 to 11, wherein R³ is -L²-OR⁶ or -L³-NR⁷R⁸, wherein L² and L³ are each independently selected from C₁₋₆ alkylene.
 17. The compound of any one of claims 1 to 16, wherein each R² is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl and —(C₁₋₄ alkylene)-OR⁴.
 18. The compound of claim 1, which is a compound selected from 3-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-Propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 1-Butyl-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, N,N-Diethyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine, 1-Butyl-N-ethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, 4-(3-((4′-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propyl)morpholine, 3-(5′-(3-(4,4-Difluoropiperidin-1-yl)propoxy)-[2,2′-bipyridin]-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(3-(Piperidin-1-ylmethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine, N-Butyl-3-methoxy-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)propanamide, N-(Cyclopropylmethyl)-N-methyl-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-amine, N1,N1-Diethyl-N3-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)propane-1,3-diamine, N-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-methyl-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-amine, N,N-Diethyl-3-(2-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)pyrimidin-5-yloxy)propan-1-amine, N1,N1-Diethyl-N3-methyl-N3-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-2,2′-bipyridin-5-yl)propane-1,3-diamine, 3-(2-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, N-Ethyl-N-phenethyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine, 2-Phenyl-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)acetamide, 3-(2-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(4′-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-[2,2′-bipyridin]-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 4-(2-((4′-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)oxy)ethyl)morpholine, N,N,1-Trimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, 3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 1-Butyl-N,N-diethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, 3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 2-(4,4-Difluoropiperidin-1-yl)-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)acetamide, N-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4 amine, 3-(2-(3-(Piperidin-1-ylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 1-Methyl-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)piperidine-4-carboxamide, 3-Phenyl-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)propanamide, 2-Cyclobutyl-N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)acetamide, N-(Piperidin-3-yl)-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridine]-4-carboxamide, 3-(5′-(3-(1H-Pyrazol-1-yl)propoxy)-[2,2′-bipyridin]-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, (1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methanol, 3-(2-(3-(Methoxymethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine, 3-(2-(1H-Pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-(Pyridin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, N-((1-Methylpiperidin-4-yl)methyl)-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridine]-4-carboxamide, N-((1-Methylpiperidin-4-yl)methyl)-4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridine]-5-carboxamide, 3-(2-(1-(1-(2,2,2-Trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-Methyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-Butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, N-Methyl-3-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-2,2′-bipyridin-5-yloxy) propan-1-amine, 1-(1-Butyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine, 3-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, N-(4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-4-yl)piperidine-3-carboxamide, 1-(2-Methoxyethyl)-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, 3-(2-(1-(2-Methoxyethyl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-Methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-(Pyridin-3-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-(Pyridin-2-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 2-(Methyl(3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propyl)amino)ethan-1-ol, 3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(2-(2-Methoxyethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, N,N-Dimethyl-3-((4′-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2′-bipyridin]-5-yl)oxy)propan-1-amine, 3-(2-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, 3-(2-(1-(2-(1-Methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, and 3-(2-(1-((1-Methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, or a salt thereof.
 19. A pharmaceutical composition which comprises a compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 20. A compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use as a medicament.
 21. A compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19, for use in the treatment of a disease associated with HDAC6.
 22. A compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19, for use in the treatment of a disease selected from cancer, an autoimmune or inflammatory disease, transplant rejection, a ciliopathy, a disease of the nervous system, a mental or behavioral disorder, an infectious disease, a cardiovascular disease, muscle atrophy and cachexia.
 23. A method for treating a disease associated with HDAC6, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
 24. A method for treating a disease selected from cancer, an autoimmune or inflammatory disease, transplant rejection, a ciliopathy, a disease of the nervous system, a mental or behavioral disorder, an infectious disease, a cardiovascular disease, muscle atrophy and cachexia, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
 25. Use of a compound of any one of claims 1 to 18, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with HDAC6.
 26. Use of a compound of any one of claims 1 to 18, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease selected from cancer, an autoimmune or inflammatory disease, transplant rejection, a ciliopathy, a disease of the nervous system, a mental or behavioral disorder, an infectious disease, a cardiovascular disease, muscle atrophy and cachexia.
 27. Use of a compound of any one of claims 1 to 18, or pharmaceutically acceptable salt thereof, for treating a disease associated with HDAC6.
 28. Use of a compound of any one of claims 1 to 18, or pharmaceutically acceptable salt thereof, for treating a disease selected from cancer, an autoimmune or inflammatory disease, transplant rejection, a ciliopathy, a disease of the nervous system, a mental or behavioral disorder, an infectious disease, a cardiovascular disease, muscle atrophy and cachexia.
 29. The compound for use according to any one of claims 20 to 22, or the pharmaceutical composition for use according to claim 21 or 22, or the method of claim 23 or 24, or the use of any one of claims 25 to 28, wherein the patient to be treated is a human.
 30. In vitro method of inhibiting HDAC6, the method comprising applying a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, to a sample.
 31. In vitro use of a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, as an HDAC6 inhibitor. 